Semaphorin gene family

ABSTRACT

A novel class of proteins, semaphorins, nucleic acids encoding semaphorins, semaphorin peptides, and methods of using semaphorins and semaphorin-encoding nucleic acids are disclosed. Semaphorin peptides and receptor agonists and antagonists provide potent modulators of nerve cell growth and regeneration. The invention provides pharmaceutical compositions, methods for screening chemical libraries for regulators of cell growth/differentiation; semaphorin gene-derived nucleic acids for use in genetic mapping, as probes for related genes, and as diagnostic reagents for genetic neurological disease; specific cellular and animal systems for the development of neurological disease therapy.

This is a division of application Ser. No. 08/121,713 filed Sep. 13,1993 now U.S. Pat. No. 5,639,856.

The research carried out in the subject application was supported inpart by grants from the National Institutes of Health. The governmentmay have rights in any patent issuing on this application.

INTRODUCTION

1. Technical Field

The technical field of this invention concerns peptides, polypeptides,and polynucleotides involved in nerve cell growth.

2. Background

The specificity of the wiring of the nervous system--the complex patternof specific synaptic connections--begins to unfold during development asthe growing tips of neurons--the growth cones--traverse long distancesto find their correct targets. Along their journey, they are confrontedby and correctly navigate a series of choice points in a remarkablyunerring way to ultimately contact and recognize their correct target.

The identification of growth cone guidance cues is to a large extent,the holy grail of neurobiology. These are the compounds that tellneurons when to grow, where to grow, and when to stop growing. Themedical applications of such compounds and their antagonists areenormous and include modulating neuronal growth regenerative capacity,treating neurodegenerative disease, and mapping (e.g. diagnosing)genetic neurological defects.

Over decades of concentrated research, various hypotheses ofchemo-attractants and repellant, labeled pathways, cell adhesionmolecules, etc. have been evoked to explain guidance. Recently, severalrecent lines of experiments suggest repulsion may play an important rolein neuron guidance and two apparently unrelated factors ("Neurite GrowthInhibitor" and "Collapsin") capable of inhibiting or collapsing growthcones have been reported.

3. Relevant Literature

For a recent review of much of the literature in this field, see Goodmanand Shatz (1993) Cell 72/Neuron 10, 77-98. A description of grasshopperfasciclin IV (now called G-Semaphorin I) appears in Kolodkin et al.(1992) Neuron 9, 831-845. Recent reports on Collapsin and Neurite GrowthInhibitor include Raper and Kapfhammer (1990) Neuron 4, 21-29, anabstract presented by Raper at the GIBCO-BRL Symposium on "Genes andDevelopment/Function of Brain" on Jul. 26, 1993 and Schwab and Caroni(1988) J Neurosci 8, 2381 and Schnell and Schwab (1990) Nature 343, 269,respectively.

SUMMARY OF THE INVENTION

A novel class of proteins, semaphorins, nucleic acids encodingsemaphorins, and methods of using semaphorins and semaphorin-encodingnucleic acids are disclosed. Semaphorins include the first known familyof human proteins which function as growth cone inhibitors and a familyof proteins involved in viral, particularly pox viral, pathogenesis andoncogenesis. Families of semaphorin-specific receptors, includingreceptors found on nerve growth cones and immune cells are alsodisclosed.

The invention provides agents, including semaphorin peptides, whichspecifically bind semaphorin receptors and agents, including semaphorinreceptor peptides, which specifically bind semaphorins. These agentsprovide potent modulators of nerve cell growth, immune responsivenessand viral pathogenesis and find use in the treatment and diagnosis ofneurological disease and neuro-regeneration, immune modulation includinghypersensitivity and graft-rejection, and diagnosis and treatment ofviral and oncological infection/diseases.

Semaphorins, semaphorin receptors, semaphorin-encoding nucleic acids,and unique portions thereof also find use variously in screeningchemical libraries for regulators of semaphorin or semaphorinreceptor-mediated cell activity, in genetic mapping, as probes forrelated genes, as diagnostic reagents for genetic neurological,immunological and oncological disease and in the production of specificcellular and animal systems for the development of neurological,immunological, oncological and viral disease therapy.

DESCRIPTION OF SPECIFIC EMBODIMENTS

The present invention discloses novel families of proteins important innerve and immune cell function: the semaphorins and the semaphorinreceptors. The invention provides agents, including semaphorin peptides,which specifically bind semaphorin receptors and agents, includingsemaphorin receptor peptides, which specifically bind semaphorins. Theseagents find a wide variety of clinical, therapeutic and research uses,especially agents which modulate nerve and/or immune cell function byspecifically mimicing or interfering with semaphorin-receptor binding.For example, selected semaphorin peptides shown to act as semaphorinreceptor antagonists are effective by competitively inhibiting nativesemaphorin association with cellular receptors. Thus, depending on thetargeted receptor, these agents can be used to block semaphorin mediatedneural cell growth cone repulsion or contact inhibition. Such agentsfind broad clinical application where nerve cell growth is indicated,e.g. traumatic injury to nerve cells, neurodegenerative disease, etc. Awide variety of semaphorin- and semaphorin receptor-specific bindingagents and methods for identifying, making and using the same aredescribed below.

Binding agents of particular interest are semaphorin peptides whichspecifically bind and antagonize a semaphorin receptor and semaphorinreceptor peptides which specifically bind a semaphorin and preventbinding to a native receptor. While exemplified primarily withsemaphorin peptides, much of the following description appliesanalogously to semaphorin receptor peptides.

The semaphorin peptides of the invention comprise a unique portion of asemaphorin and have semaphorin binding specificity. A "unique portion"of a semaphorin has an amino acid sequence unique to that disclosed inthat it is not found in any previously known protein. Thus a uniqueportion has an amino acid sequence length at least long enough to definea novel peptide. Unique semaphorin portions are found to vary from about5 to about 25 residues, preferably from 5 to 10 residues in length,depending on the particular amino acid sequence. Unique semaphorinportions are readily identified by comparing the subject semaphorinportion sequences with known peptide/protein sequence data bases.Preferred unique portions derive from the semaphorin domains (whichexclude the Ig-like, intracellular and transmembrane domains as well asthe signal sequences) of the disclosed semaphorin sequences, especiallyregions that bind the semaphorin receptor, especially that of the humanvarieties. Preferred semaphorin receptor unique portions derive from thesemaphorin binding domains, especially regions with residues whichcontact the semaphorin ligand, especially that of the human varieties.Particular preferred peptides are further described herein.

The subject peptides may be free or coupled to other atoms or molecules.Frequently the peptides are present as a portion of a larger polypeptidecomprising the subject peptide where the remainder of the polypeptideneed not be semaphorin- or semaphorin receptor-derived. Alternatively,the subject peptide may be present as a portion of a "substantiallyfull-length" semaphorin domain or semaphorin receptor sequence whichcomprises or encodes at least about 200, preferably at least about 250,more preferably at least about 300 amino acids of a disclosedsemaphorin/receptor sequence. Thus the invention also providespolypeptides comprising a sequence substantially similar to that of asubstantially full-length semaphorin domain or a semaphorin receptor."Substantially similar" sequences share at least about 40%, morepreferably at least about 60%, and most preferably at least about 80%sequence identity. Where the sequences diverge, the differences aregenerally point insertions/deletions or conservative substitutions, i.e.a cysteine/threonine or serine substitution, an acidic/acidic orhydrophobic/hydrophobic amino acid substitution, etc.

The subject semaphorin peptides/polypeptides are "isolated", meaningunaccompanied by at least some of the material with which they areassociated in their natural state. Generally, an isolatedpeptide/polypeptide constitutes at least about 1%, preferably at leastabout 10%, and more preferably at least about 50% by weight of the totalpeptide/protein in a given sample. By pure peptide/polypeptide isintended at least about 90%, preferably at least 95%, and morepreferably at least about 99% by weight of total peptide/protein.Included in the subject peptide/polypeptide weight are any atoms,molecules, groups, or polymers covalently coupled to the subjectsemaphorin/receptor peptide/polypeptide, especially peptides, proteins,detectable labels, glycosylations, phosphorylations, etc.

The subject peptides/polypeptides may be isolated or purified in avariety of ways known to those skilled in the art depending on whatother components are present in the sample and to what, if anything, thepeptide/polypeptide is covalently linked. Purification methods includeelectrophoretic, molecular, immunological and chromatographictechniques, especially affinity chromatography and RP-HPLC in the casepeptides. For general guidance in suitable purification techniques, seeScopes, R., Protein Purification, Springer-Verlag, NY (1982).

The subject peptides/polypeptides generally comprise naturally occurringamino acids but D-amino acids or amino acid mimetics coupled by peptidebonds or peptide bond mimetics may also be used. Amino acid mimetics areother than naturally occurring amino acids that conformationally mimicthe amino acid for the purpose of the requisite semaphorin/receptorbinding specificity. Suitable mimetics are known to those of ordinaryskill in the art and include β-γ-δ amino and imino acids,cyclohexylalanine, adamantylacetic acid, etc., modifications of theamide nitrogen, the α-carbon, amide carbonyl, backbone modifications,etc. See, generally, Morgan and Gainor (1989) Ann. Repts. Med. Chem 24,243-252; Spatola (1983) Chemistry and Biochemistry of Amino Acids,Peptides and Proteins, Vol VII (Weinstein) and Cho et. al (1993) Science261, 1303-1305 for the synthesis and screening of oligocarbamates.

The subject semaphorin peptides/polypeptides have a "semaphorin bindingspecificity" meaning that the subject peptide/polypeptide retains amolecular conformation specific to one or more of the disclosedsemaphorins and specifically recognizable by a semaphorin-specificreceptor, antibody, etc. As such, a semaphorin binding specificity maybe provided by a semaphorin-specific immunological epitope, lectinbinding site, etc., and preferably, a receptor binding site.Analogously, the semaphorin receptor peptides/polypeptides have a"semaphorin receptor binding specificity" meaning that thesepeptides/polypeptides retain a molecular conformation specific to one ormore of the disclosed semaphorin receptors and specifically recognizableby a semaphorin, a receptor-specific antibody, etc.

"Specific binding" is empirically determined by contacting, for examplea semaphorin-derived peptide with a mixture of components andidentifying those components that preferentially bind the semaphorin.Specific binding is most conveniently shown by competition with labeledligand using recombinant semaphorin peptide either in vitro or incellular expression systems as disclosed herein. Generally, specificbinding of the subject semaphorin has binding affinity of 10⁻⁶ M,preferably 10⁻⁸ M, more preferably 10⁻¹⁰ M, under in vitro conditions asexemplified below.

The peptides/polypeptides may be modified or joined to other compoundsusing physical, chemical, and molecular techniques disclosed or citedherein or otherwise known to those skilled in the relevant art to affecttheir semaphorin binding specificity or other properties such assolubility, membrane transportability, stability, binding specificityand affinity, chemical reactivity, toxicity, bioavailability,localization, detectability, in vivo half-life, etc. as assayed bymethods disclosed herein or otherwise known to those of ordinary skillin the art. For example, point mutations are introduced by site directedmutagenesis of nucleotides in the DNA encoding the disclosed semaphorinpolypeptides or in the course of in vitro peptide synthesis.

Other modifications to further modulate binding specificity/affinityinclude chemical/enzymatic intervention (e.g. fatty acid-acylation,proteolysis, glycosylation) and especially where the peptide/polypeptideis integrated into a larger polypeptide, selection of a particularexpression host, etc. In particular, many of the disclosed semaphorinpeptides contain serine and threonine residues which are phosphorylatedor dephosphorylated. See e.g. methods disclosed in Roberts et al. (1991)Science 253, 1022-1026 and in Wegner et al. (1992) Science 256, 370-373.Amino and/or carboxyl termini may be functionalized e.g., for the aminogroup, acylation or alkylation, and for the carboxyl group,esterification or amidification, or the like. Many of the disclosedsemaphorin peptides/polypeptides also contain glycosylation sites andpatterns which may disrupted or modified, e.g. by enzymes likeglycosidases or used to purify/identify the receptor, e.g. with lectins.For instance, N or O-linked glycosylation sites of the disclosedsemaphorin peptides may be deleted or substituted for by another basicamino acid such as Lys or His for N-linked glycosylation alterations, ordeletions or polar substitutions are introduced at Ser and Thr residuesfor modulating O-linked glycosylation. Glycosylation variants are alsoproduced by selecting appropriate host cells, e.g. yeast, insect, orvarious mammalian cells, or by in vitro methods such as neuraminidasedigestion. Useful expression systems include COS-7, 293, BHK, CHO, TM4,CV1, VERO-76, HELA, MDCK, BRL 3A, W138, Hep G2, MMT 060562, TRI cells,baculovirus systems, for examples. Other covalent modifications of thedisclosed semaphorin peptides/polypeptides may be introduced by reactingthe targeted amino acid residues with an organic derivatizing (e.g.methyl-3- (p-azido-phenyl)dithio!propioimidate) or crosslinking agent(e.g. 1,1-bis(diazoacetyl)-2-phenylethane) capable of reacting withselected side chains or termini. For therapeutic and diagnosticlocalization, semaphorins and peptides thereof may be labeled directly(radioisotopes, fluorescers, etc.) or indirectly with an agent capableof providing a detectable signal, for example, a heart muscle kinaselabeling site.

The following are 14 classes of preferred semaphorin peptides wherebracketed positions may be occupied by any one of the residues containedin the brackets and "Xaa" signifies that the position may be occupied byany one of the 20 naturally encoded amino acids (see, Table 1). Theseenumerated peptides maintain highly conserved structures which provideimportant semaphorin binding specificities;

(a) AspGlu!Cys GlnLysArgAlaAsn!Asn TyrPheVal!Ile (SEQ ID NO:1)

Cys GlnLysArgAlaAsn!Asn TyrPheVal!Ile ArgLysGlnThr! (SEQ ID NO:2)

(b)CysGlyThr AsnGly! AlaSerAsn! TyrPheHisGly! LysArgHisAsnGln! (SEQ IDNO:3)

CysGlyThr AsnGly! AlaSerAsn!XaaXaaPro (SEQ ID NO:4)

CysGlyThr AsnGly!XaaXaaXaaProXaa CysAsp! (SEQ ID NO:5)

CysGlyThrXaaXaaXaaXaaProXaa CysAsp!XaaXaa TyrIle! (SEQ ID NO:6)

(c) ArgIleGlnVal! GlyAla! LeuValLys! CysSer!Pro PheTyr! AspAsn! (SEQ IDNO:7)

CysSer!Pro PheTyr! AspAsn!Pro AspGluArgLys! HisLeuAsp! (SEQ ID NO:8)

GlyXaa GlyAla!Xaa CysSer!ProTyr AspAsn!Pro (SEQ ID NO:9)

(d) Leu PheTyr!Ser GlyAla!Thr ValAsnAla!Ala (SEQ ID NO:10)

Leu PheTyr!SerXaaThrXaaAla AspGlu! PheTyr! (SEQ ID NO:11)

PheTyr!Ser GlyAla!Thr ValAsnAla!Ala AspGlu! PheTyr! (SEQ ID NO:12)

(e) Leu AsnAsp! AlaLys!ProAsnPheVal (SEQ ID NO:13)

(f) PhePhePheArgGlu (SEQ ID NO:14)

PhePhe PheTyr!ArgGlu ThrAsn! (SEQ ID NO:15)

PhePheArgGlu ThrAsn!Ala (SEQ ID NO:16)

Phe PheTyr!ArgGlu ThrAsn!Ala (SEQ ID NO:17)

TyrPhePhe PheTyr!ArgGlu (SEQ ID NO:18)

PheTyr!PhePhe PheTyr!ArgGlu (SEQ ID NO:19) PheTyr! PheTyr! PheTyr!ArgGluThrAsn!Ala (SEQ ID NO:20)

IleVal! PheTyr!Phe PheTyr! PheTyr!ArgGlu (SEQ ID NO:21)

Asp LysPheTyr!Val PheTyr! PheTyrIleLeu! PheTyrIleLeu! PheTyr! (SEQ IDNO:22)

ValIle! PheTyr! PheTyrIleLeu! PheTyrIleLeu!Phe ArgThr!Xaa ThrAsn! (SEQID NO:23)

ValIle! PheTyr! PheTyrIleLeu! PheTyrIleLeu! PheTyr! ArgThr! GluAspVal!ThrAsn! (SEQ ID NO:24)

(g) Glu PheTyr!IleAsn CysSer!GlyLys (SEQ ID NO:25)

PheTyr!IleAsnCysGlyLys AlaValIle! (SEQ ID NO:26)

(h) Arg ValIle! AlaGly! ArgGln! ValIle!CysLys (SEQ ID NO:27)

Arg ValIle!Xaa ArgGln! ValIle!CysXaaXaaAsp (SEQ ID NO:28)

GlyLys ValAlaIle!XaaXaaXaaArg ValAlaIle!XaaXaaXaaCysLys (SEQ ID NO:29)

(i) ArgLysAsn!Trp ThrAlaSer! ThrAlaSer! PheTyrLeu!Leu LysArg! (SEQ IDNO:30)

PheTyr!Leu LysArg! AlaSer!ArgLeu AsnIle!Cys (SEQ ID NO:31)

AsnIle!CysSer IleVal! ProSer!Gly (SEQ ID NO:32)

Trp ThrAlaSer! ThrAlaSer! PheTyrLeu!LeuLys AlaSerValIleLeu!XaaLeu (SEQID NO:33)

Trp ThrAlaSer! ThrAlaSer!XaaLeuLysXaaXaaLeuXaaCys (SEQ ID NO:34)

TrpXaa ThrSer!XaaLeuLysXaaXaaLeuXaaCys (SEQ ID NO:35)

(j) PheTyr! PheTyr! AsnAsp!GluIleGlnSer (SEQ ID NO:36)

PheTyr!Pro PheTyr! PheTyr! PheTyr! AsnAsp!Glu (SEQ ID NO:37)

(k) GlySerAla ValIleLeu!CysXaa PheTyr! (SEQ ID NO:38)

SerAla ValIleLeu!CysXaa PheTyr!XaaMet (SEQ ID NO:39)

(l) AsnSer AsnAla!TrpLeu ProAla!Val (SEQ ID NO:40)

(m) ValLeuIle!Pro GluAspTyrSerPhe!ProArgProGly (SEQ ID NO:41)

ValLeuIle!ProXaaPro ArgAla!ProGlyXaaCys (SEQ ID NO:42)

Pro GluAspTyrSerPhe!ProArgProGly ThrGlnSer!Cys (SEQ ID NO:43)

(n) AspPro HisPheTyr!Cys AlaGly!Trp (SEQ ID NO:44)

Pro HisPheTyr!Cys AlaGly!TrpAsp (SEQ ID NO:45)

AspProXaaCys AlaGly!TrpAsp (SEQ ID NO:46)

CysXaaXaaXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:47)

CysXaaXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:48)

CysXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:49)

CysXaaXaaCysXaaXaaXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:50)

CysXaaXaaCysXaaXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:51)

CysXaaXaaCysXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:52)

The following peptides represent particularly preferred members of eachclass:

(a) AspCysGlnAsnTyrIle (SEQ ID NO:67)

(b) CysGlyThr AsnGly! AlaSer!XaaXaaPro (SEQ ID NO:68)

(c) GlyXaa SerCys!ProTyrAspPro (SEQ ID NO:69)

(d) LeuTyrSerGlyThr ValAsnAla!Ala (SEQ ID NO:70)

(e) LeuAsnAlaProAsnPheVal (SEQ ID NO:71)

(f) PheTyr!PhePhe PheTyr!ArgGlu (SEQ ID NO:19)

(g) Glu PheTyr!IleAsn CysSer!GlyLys (SEQ ID NO:25)

(h) Arg ValIle!AlaArgValCysLys (SEQ ID NO:72)

(i) Trp ThrAla! ThrSer! PheTyr!LeuLys AlaSer!ArgLeu (SEQ ID NO:73)

(j) ProPheTyrPhe AsnAsp!GluIleGlnSer (SEQ ID NO:74)

(k) GlySerAlaValCysXaa PheTyr! (SEQ ID NO:75)

(l) AsnSerAsnTrpLeu ProAla!Val (SEQ ID NO:76)

(m) Pro GluAsp!ProArgProGly ThrGlnSer!Cys (SEQ ID NO:77)

(n) AspProTyrCys AlaGly!TrpAsp (SEQ ID NO:78)

The following 14 classes are preferred peptides which exclude semaphorinpeptides encoded in open reading frames of Variola major or Vacciniaviruses.

(a) AspGlu!Cys GlnLysArgAlaAsn!Asn TyrPheVal!Ile (SEQ ID NO:01)

Cys GlnLysArgAlaAsn!Asn TyrPheVal!Ile ArgLysGlnThr! (SEQ ID NO:02)

(b) CysGlyThr AsnGly! AlaSer! TyrPheHisGly! LysArgHisAsnGln! (SEQ IDNO:79)

CysGlyThr AsnGly! AlaSerAsn! TyrPheHis! LysArgHisAsnGln! (SEQ ID NO:80)

CysGlyThr AsnGly! AlaSer!XaaXaaPro (SEQ ID NO:81)

(c) ArgIleGlnVal! GlyAla! LeuValLys! CysSer!Pro PheTyr! AspAsn! (SEQ IDNO:07)

CysSer!Pro PheTyr! AspAsn!Pro AspGluArgLys! HisLeuAsp! (SEQ ID NO:08)

GlyXaa GlyAla!Xaa CysSer!ProTyr AspAsn!Pro (SEQ ID NO:09)

(d) Leu PheTyr!Ser GlyAla!Thr ValAsnAla!Ala (SEQ ID NO:10)

Leu PheTyr!SerXaaThrXaaAla AspGlu! PheTyr! (SEQ ID NO:11)

PheTyr!Ser GlyAla!Thr ValAsnAla!Ala AspGlu! PheTyr! (SEQ ID NO:12)

(e) Leu AsnAsp! AlaLys!ProAsnPheVal (SEQ ID NO:13)

(f) PhePhePheArgGlu (SEQ ID NO:14)

PhePhe PheTyr!ArgGlu ThrAsn! (SEQ ID NO:15)

PhePheArgGlu ThrAsn!Ala (SEQ ID NO:16)

Phe PheTyr!ArgGlu ThrAsn!Ala (SEQ ID NO:17)

TyrPhePhe PheTyr!ArgGlu (SEQ ID NO:18)

PheTyr!PhePhe PheTyr!ArgGlu (SEQ ID NO:19)

PheTyr! PheTyr! PheTyr!ArgGlu ThrAsn!Ala (SEQ ID NO:20)

IleVal! PheTyr!Phe PheTyr! PheTyr!ArgGlu (SEQ ID NO:21)

Asp LysPheTyr!Val PheTyr! PheTyrLeu! PheTyrIleLeu! PheTyr! (SEQ IDNO:22)

Asp LysPheTyr!Val PheTyr! PheTyrIleLeu! PheTyrIle! PheTyr! (SEQ IDNO:82)

ValIle! PheTyr! PheTyrLeu! PheTyrIleLeu!Phe ArgThr!Xaa ThrAsn! (SEQ IDNO:83)

ValIle! PheTyr! PheTyrIleLeu! PheTyrIle!Phe ArgThr!Xaa ThrAsn! (SEQ IDNO:84)

ValIle! PheTyr! PheTyrIleLeu! PheTyrIleLeu!PheArgXaa ThrAsn! (SEQ IDNO:85)

ValIle! PheTyr! PheTyrLeu! PheTyrIleLeu! PheTyr! ArgThr! GluAspVal!ThrAsn! (SEQ ID NO:86)

(g) Glu PheTyr!IleAsn CysSer!GlyLys (SEQ ID NO:25)

PheTyr!IleAsnCysGlyLys AlaValIle! (SEQ ID NO:26)

(h) Arg ValIle! AlaGly! ArgGln! ValIle!CysLys (SEQ ID NO:27)

Arg ValIle!Xaa ArgGln! ValIle!CysXaaXaaAsp (SEQ ID NO:28)

GlyLys ValAlaIle!XaaXaaXaaArg ValAlaIle!XaaXaaXaaCysLys (SEQ ID NO:29)

(i) ArgLysAsn!Trp ThrAla! ThrAlaSer! PheTyrLeu!Leu LysArg! (SEQ IDNO:87)

PheTyr!Leu LysArg! AlaSer!ArgLeu AsnIle!Cys (SEQ ID NO:31)

AsnIle!CysSer IleVal! ProSer!Gly (SEQ ID NO:32)

Trp ThrAla! ThrAlaSer! PheTyrLeu!LeuLys AlaSerValIleLeu!XaaLeu (SEQ IDNO:88)

Trp AlaSer! ThrAlaSer! PheTyrLeu!LeuLys AlaSerIleLeu!XaaLeu (SEQ IDNO:89)

Trp Ala! ThrAlaSer!XaaLeuLysXaaXaaLeuXaaCys (SEQ ID NO:90)

(j) PheTyr! PheTyr! AsnAsp!GluIleGlnSer (SEQ ID NO:36)

PheTyr!Pro PheTyr! PheTyr! PheTyr! AsnAsp!Glu (SEQ ID NO:37)

(k) GlySerAla ValIleLeu!CysXaa PheTyr! (SEQ ID NO:38)

SerAla ValIle!CysXaa PheTyr!XaaMet (SEQ ID NO:39)

(l) AsnSer AsnAla!TrpLeu ProAla!Val (SEQ ID NO:40)

(m) ValLeuIle!Pro GluAspTyrSerPhe!ProArgProGly (SEQ ID NO:41)

ValLeuIle!ProXaaProArgProGlyXaaCys (SEQ ID NO:91)

Pro GluAspTyrSerPhe!ProArgProGly ThrGlnSer!Cys (SEQ ID NO:43)

(n) AspPro HisPheTyr!Cys AlaGly!Trp (SEQ ID NO:44)

Pro HisPheTyr!Cys AlaGly!TrpAsp (SEQ ID NO:45)

AspProXaaCys AlaGly!TrpAsp (SEQ ID NO:46)

CysXaaXaaXaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:47)

CysXaaXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:48)

CysXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:49)

CysXaaXaaCysXaaXaaXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:50)

CysXaaXaaCysXaaXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:51)

CysXaaXaaCysXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:52)

The following 2 classes are preferred peptides which exclude semaphorinpeptides encoded in open reading frames of Variola major or Vacciniaviruses Grasshopper Semaphorin I.

(f) TyrPhePhe PheTyr!ArgGlu (SEQ ID NO:18)

Asp LysTyr!Val PheTyr! PheTyrLeu! PheTyrIleLeu! PheTyr! (SEQ ID NO:92)

Asp LysTyr!Val PheTyr! PheTyrIleLeu! PheTyrIle! PheTyr! (SEQ ID NO:93)

ValIle!Tyr PheTyrLeu! PheTyrIleLeu!Phe ArgThr!Xaa ThrAsn! (SEQ ID NO:94)

ValIle!Tyr PheTyrIleLeu! PheTyrIle!Phe ArgThr!Xaa ThrAsn! (SEQ ID NO:95)

ValIle!Tyr PheTyrIleLeu! PheTyrIleLeu!PheArgXaa ThrAsn! (SEQ ID NO:96)

Val PheTyr! PheTyrLeu! PheTyrIleLeu! PheTyr! ArgThr! GluAspVal!ThrAsn!(SEQ ID NO:97)

Val PheTyr! PheTyrIleLeu! PheTyrIle! PheTyr! ArgThr! GluAspVal!ThrAsn!(SEQ ID NO:98)

Val PheTyr! PheTyrIleLeu! PheTyrIleLeu! PheTyr!Arg GluAspVal!ThrAsn!(SEQ ID NO:99)

(n) CysXaaXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:48)

CysXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:49)

CysXaaXaaCysXaaXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:51)

CysXaaXaaCysXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:52)

The following 5 classes include peptides which encompass peptidesencoded in open reading frames of Variola major or Vaccinia viruses.Accordingly, in the event that these viral peptides are not novel perse, the present invention discloses a hitherto unforseen andunforseeable utility for these peptides as immunosuppressants andtargets of anti-viral therapy.

(b) CysGlyThr AsnGly! AlaSerAsn! TyrPheHisGly! LysArgHisAsnGln! (SEQ IDNO:03)

CysGlyThr AsnGly! AlaSerAsn!XaaXaaPro (SEQ ID NO:04)

CysGlyThr AsnGly!XaaXaaXaaProXaa CysAsp! (SEQ ID NO:05)

CysGlyThrXaaXaaXaaXaaProXaa CysAsp!XaaXaa TyrIle! (SEQ ID NO:06)

(f) Asp LysPheTyr!Val PheTyr! PheTyrIleLeu! PheTyrIleLeu! PheTyr! (SEQID NO:22)

ValIle! PheTyr! PheTyrIleLeu! PheTyrIleLeu!Phe ArgThr!Xaa ThrAsn! (SEQID NO:23)

Val PheTyr! PheTyrIleLeu! PheTyrIleLeu! PheTyr! ArgThr! GluAspVal!ThrAsn! (SEQ ID NO:100)

(i) ArgLysAsn!Trp ThrAlaSer! ThrAlaSer! PheTyrLeu!Leu LysArg! (SEQ IDNO:30)

Trp ThrAlaSer! ThrAlaSer! PheTyrLeu!LeuLys AlaSerValIleLeu!XaaLeu (SEQID NO:33)

Trp ThrAlaSer! ThrAlaSer!XaaLeuLysXaaXaaLeuXaaCys (SEQ ID NO:34)

TrpXaa ThrSer!XaaLeuLysXaaXaaLeuXaaCys (SEQ ID NO:35)

(k) SerAla ValIleLeu!CysXaa PheTyr!XaaMet (SEQ ID NO:39)

(m) ValLeuIle!ProXaaPro ArgAla!ProGlyXaaCys (SEQ ID NO:42)

The disclosed semaphorin sequence data are used to define a wide varietyof other semaphorin- and semaphorin receptor-specific binding agentsusing immunologic, chromatographic or synthetic methods available tothose skilled in the art.

Of particular significance are peptides comprising unique portions ofsemaphorin-specific receptors and polypeptides comprising a sequencesubstantially similar to that of a substantially full-length semaphorinreceptor. Using semaphorin peptides, these receptors are identified by avariety of techniques known to those skilled in the art where a ligandto the target receptor is known, including expression cloning as set outin the exemplification below. For other examples of receptor isolationwith known ligand using expression cloning, see, Staunton et al (1989)Nature 339, 61; Davis et al (1991) Science 253, 59; Lin et al (1992)Cell 68, 775; Gearing et al (1989) EMBO 8, 3667; Aruffo and Seed (1987)PNAS 84, 8573 and references therein. Generally, COS cells aretransfected to express a cDNA library or PCR product and cells producingpeptides/polypeptides which bind a semaphorin/receptorpeptide/polypeptide are isolated. For neurosemaphorin receptors, fetalbrain cDNA libraries are preferred; for immunosemaphorin receptors,libraries derived from activated lymphoid or myeloid cell lines ortissue derived from sites of inflammation or delayed-typehypersensitivity are preferred; and for semaphorin and semaphorinreceptor variants used by tumor cells to evade immune surveilance orsuppress an immune response (oncosemaphorins), libraries derived fromcancerous tissue or tumor cell lines resistant to the host immune systemare preferred. Alternatively, PCR primers based upon knownsemaphorin/receptor sequences such as those disclosed herein are used toamplify PCR product from such tissues/cells. Other receptor/ligandisolation methods using immobilized ligand or antibody are known tothose skilled in the art.

Semaphorin receptor peptides with receptor binding specificity areidentified by a variety of ways including having conserved consensussequences with other semaphorin receptors, by crosslinking to ligand orreceptor-specific antibody, or preferably, by screening such peptidesfor semaphorin binding or disruption of semaphorin-receptor binding.Methods for identifying semaphorin receptor peptides with the requisitebinding activity are described herein or otherwise known to thoseskilled in the art. By analogous methods, semaphorin receptor peptidesare used to define additional semaphorin peptides with semaphorinbinding specificity, particularly receptor specificity.

The various semaphorin and semaphorin receptor peptides are used todefine functional domains of semaphorins, identify compounds thatassociate with semaphorins, design compounds capable of modulatingsemaphorin-mediated nerve and immune cell function, and defineadditional semaphorin and semaphorin receptor-specific binding agents.For example, semaphorin mutants, including deletion mutants aregenerated from the disclosed semaphorin sequences and used to identifyregions important for specific protein-ligand or protein-proteininteractions, for example, by assaying for the ability to mediaterepulsion or preclude aggregation in cell-based assays as describedherein. Further, x-ray crystallographic data of the disclosed proteinare used to rationally design binding molecules of determined structureor complementarity for modulating growth cone growth and guidance.

Additional semaphorin- and receptor-specific agents include specificantibodies that can be modified to a monovalent form, such as Fab, Fab',or Fv, specifically binding oligopeptides or oligonucleotides and mostpreferably, small molecular weight organic receptor antagonists. Forexample, the disclosed semaphorin and receptor peptides are used asimmunogens to generate semaphorin- and receptor-specific polyclonal ormonoclonal antibodies. See, Harlow and Lane (1988) Antibodies, ALaboratory Manual, Cold Spring Harbor Laboratory, for general methods.Anti-idiotypic antibody, especially internal imaging anti-ids are alsoprepared using the disclosures herein.

In addition to semaphorin and semaphorin-receptor derived polypeptidesand peptides, other prospective agents are screened from large librariesof synthetic or natural compounds. For example, numerous means areavailable for random and directed synthesis of saccharide, peptide, andnucleic acid based compounds. Alternatively, libraries of naturalcompounds in the form of bacterial, fungal, plant and animal extractsare available or readily producible. Additionally, natural andsynthetically produced libraries and compounds are readily modifiedthrough conventional chemical, physical, and biochemical means. See,e.g. Houghten et al. and Lam et al (1991) Nature 354, 84 and 81,respectively and Blake and Litzi-Davis (1992), Bioconjugate Chem 3, 510.

Useful agents are identified with a range of assays employing a compoundcomprising the subject peptides or encoding nucleic acids. A widevariety of in vitro, cell-free binding assays, especially assays forspecific binding to immobilized compounds comprising semaphorin orsemaphorin receptor peptide find convenient use. While less preferred,cell-based assays may be used to determine specific effects ofprospective agents on semaphorin-receptor binding may be assayed.Optionally, the intracellular C-terminal domain is substituted with asequence encoding a oligopeptide or polypeptide domain that provides adetectable intracellular signal upon ligand binding different from thenatural receptor. Useful intracellular domains include those of thehuman insulin receptor and the TCR, especially domains with kinaseactivity and domains capable of triggering calcium influx which isconveniently detected by fluorimetry by preloading the host cells withFura-2. More preferred assays involve simple cell-free in vitro bindingof candidate agents to immobilized semaphorin or receptor peptides, orvice versa. See, e.g. Fodor et al (1991) Science 251, 767 for lightdirected parallel synthesis method. Such assays are amenable toscale-up, high throughput usage suitable for volume drug screening.

Useful agents are typically those that bind to a semaphorin or disruptthe association of a semaphorin with its receptor. Preferred agents aresemaphorin-specific and do not cross react with other neural or lymphoidcell membrane proteins. Useful agents may be found within numerouschemical classes, though typically they are organic compounds;preferably small organic compounds. Small organic compounds have amolecular weight of more than 150 yet less than about 4,500, preferablyless than about 1500, more preferably, less than about 500. Exemplaryclasses include peptides, saccharides, steroids, heterocyclics,polycyclics, substituted aromatic compounds, and the like.

Selected agents may be modified to enhance efficacy, stability,pharmaceutical compatibility, and the like. Structural identification ofan agent may be used to identify, generate, or screen additional agents.For example, where peptide agents are identified, they may be modifiedin a variety of ways as described above, e.g. to enhance theirproteolytic stability. Other methods of stabilization may includeencapsulation, for example, in liposomes, etc.

The subject binding agents may be prepared in a variety of ways known tothose skilled in the art. For example, peptides under about 60 aminoacids can be readily synthesized today using conventional commerciallyavailable automatic synthesizers. Alternatively, DNA sequences may beprepared encoding the desired peptide and inserted into an appropriateexpression vector for expression in a prokaryotic or eukaryotic host. Awide variety of expression vectors are available today and may be usedin conventional ways for transformation of a competent host forexpression and isolation. If desired, the open reading frame encodingthe desired peptide may be joined to a signal sequence for secretion, soas to permit isolation from the culture medium. Methods for preparingthe desired sequence, inserting the sequence into an expression vector,transforming a competent host, and growing the host in culture forproduction of the product may be found in U.S. Pat. Nos. 4,710,473,4,711,843 and 4,713,339.

For therapeutic uses, the compositions and agents disclosed herein maybe administered by any convenient way, preferably parenterally,conveniently in a pharmaceutically or physiologically acceptablecarrier, e.g., phosphate buffered saline, saline, deionized water, orthe like. Typically, the compositions are added to a retainedphysiological fluid such as blood or synovial fluid. For CNSadministration, a variety of techniques are available for promotingtransfer of the therapeutic across the blood brain barrier includingdisruption by surgery or injection, drugs which transciently openadhesion contact between CNS vasculature endothelial cells, andcompounds which facilitate translocation through such cells. Asexamples, many of the disclosed therapeutics are amenable to directlyinjected or infused, contained within implants e.g. osmotic pumps,grafts comprising appropriately transformed cells. Generally, the amountadministered will be empirically determined, typically in the range ofabout 10 to 1000 μg/kg of the recipient. For peptide agents, theconcentration will generally be in the range of about 50 to 500 μg/ml inthe dose administered. Other additives may be included, such asstabilizers, bactericides, etc. These additives will be present inconventional amounts.

The invention provides isolated nucleic acid sequences encoding thedisclosed semaphorin and semaphorin receptor peptides and polypeptides,including sequences substantially identical to sequences encoding suchpolypeptides. An "isolated" nucleic acid sequence is present as otherthan a naturally occurring chromosome or transcript in its natural stateand typically is removed from at least some of the nucleotide sequenceswith which it is normally associated with on a natural chromosome. Acomplementary sequence hybridizes to a unique portion of the disclosedsemaphorin sequence under low stringency conditions, for example, at 50°C. and SSC (0.9M saline/0.09M sodium citrate) and that remains boundwhen subject to washing at 55° C. with SSC. Regions of non-identity ofcomplementary nucleic acids are preferably or in the case of homologousnucleic acids, a nucleotide change providing a redundant codon. Apartially pure nucleotide sequence constitutes at least about 5%,preferably at least about 30%, and more preferably at least about 90% byweight of total nucleic acid present in a given fraction.

Unique portions of the disclosed nucleic acid sequence are of lengthsufficient to distinguish previously known nucleic acid sequences. Thus,a unique portion has a nucleotide sequence at least long enough todefine a novel oligonucleotide. Preferred nucleic acid portions encode aunique semaphorin peptide. The nucleic acids of the invention andportions thereof, other than those used as PCR primers, are usually atleast about 60 bp and usually less than about 60 kb in length. PCRprimers are generally between about 15 and 100 nucleotides in length.

Nucleotide (cDNA) sequences encoding several full length semaphorins aredisclosed in herein. The invention also provides for the disclosedsequences modified by transitions, transversions, deletions, insertions,or other modifications such as alternative splicing and also providesfor genomic semaphorin sequences, and gene flanking sequences, includingregulatory sequences; included are DNA and RNA sequences, sense andantisense. Preferred DNA sequence portions include portions encoding thepreferred amino acid sequence portions disclosed above. For antisenseapplications where the inhibition of semaphorin expression is indicated,especially useful oligonucleotides are between about 10 and 30nucleotides in length and include sequences surrounding the disclosedATG start site, especially the oligonucleotides defined by the disclosedsequence beginning about 5 nucleotides before the start site and endingabout 10 nucleotides after the disclosed start site. Other especiallyuseful semaphorin mutants involve deletion or substitution modificationsof the disclosed cytoplasmic C-termini of transmembrane semaphorins.Accordingly, semaphorin mutants with semaphorin binding affinities butwith altered intracellular signal transduction capacities are produced.

For modified semaphorin-encoding sequences or related sequences encodingproteins with semaphorin-like functions, there will generally besubstantial sequence identity between at least a segment thereof and asegment encoding at least a portion of the disclosed semaphorinsequence, preferably at least about 60%, more preferably at least 80%,most preferably at least 90% identity. Homologous segments areparticularly within semaphorin domain-encoding regions and regionsencoding protein domains involved in protein-protein, particularlysemaphorin-receptor interactions and differences within such segmentsare particularly conservative substitutions.

Typically, the invention's semaphorin peptide encoding polynucleotidesare associated with heterologous sequences. Examples of suchheterologous sequences include regulatory sequences such as promoters,enhancers, response elements, signal sequences, polyadenylationsequences, etc., introns, 5' and 3' noncoding regions, etc. Other usefulheterologous sequences are known to those skilled in the art orotherwise disclosed references cited herein. According to a particularembodiment of the invention, portions of the semaphorin encodingsequence are spliced with heterologous sequences to produce soluble,secreted fusion proteins, using appropriate signal sequences andoptionally, a fusion partner such as β-Gal.

The disclosed sequences are also used to identify and isolate othernatural semaphorins and analogs. In particular, the disclosed nucleicacid sequences are used as hybridization probes under low-stringency orPCR primers, e.g. oligonucleotides encoding functional semaphorindomains are ³² P-labeled and used to screen λcDNA libraries at lowstringency to identify similar cDNAs that encode proteins with relatedfunctional domains. Additionally, nucleic acids encoding at least aportion of the disclosed semaphorin are used to characterize tissuespecific expression of semaphorin as well as changes of expression overtime, particularly during organismal development or cellulardifferentiation.

The semaphorin encoding nucleic acids can be subject to alternativepurification, synthesis, modification, sequencing, expression,transfection, administration or other use by methods disclosed instandard manuals such as Molecular Cloning, A Laboratory Manual (2ndEd., Sambrook, Fritsch and Maniatis, Cold Spring Harbor), CurrentProtocols in Molecular Biology (Eds. Aufubel, Brent, Kingston, More,Feidman, Smith and Stuhl, Greene Publ. Assoc., Wiley-Interscience, NY,N.Y., 1992) or that are otherwise known in the art. For example, thenucleic acids can be modified to alter stability, solubility, bindingaffinity and specificity, etc. semaphorin-encoding sequences can beselectively methylated, etc. The nucleic acid sequences of the presentinvention may also be modified with a label capable of providing adetectable signal, either directly or indirectly. Exemplary labelsinclude radioisotopes, fluorescers, biotinylation, etc.

The invention also provides vectors comprising nucleic acids encodingsemaphorin peptides, polypeptides or analogs. A large number of vectors,including plasmid and viral vectors, have been described for expressionin a variety of eukaryotic and prokaryotic hosts. Advantageously,vectors may also include a promotor operably linked to thesemaphorin-encoding portion. Vectors will often include one or morereplication systems for cloning or expression, one or more markers forselection in the host, e.g. antibiotic resistance. The insertedsemaphorin coding sequences may be synthesized, isolated from naturalsources, prepared as hybrids, etc. Suitable host cells may betransformed/transfected/infected by any suitable method includingelectroporation, CaCl₂ mediated DNA uptake, viral infection,microinjection, microprojectile, or other methods.

Appropriate host cells include bacteria, archebacteria, fungi,especially yeast, and plant and animal cells, especially mammaliancells. Of particular interest are E. coli, B. subtilis, Saccharomycescerevisiae, SP9 cells, C129 cells, 293 cells, Neurospora, and CHO, COS,HeLa cells, immortalized mammalian myeloid and lymphoid cell lines, andpluripotent cells, especially mammalian ES cells and zygotes. Preferredreplication systems include M13, ColE1, SV40, baculovirus, lambda,adenovirus, AAV, BPV, etc. A large number of transcription initiationand termination regulatory regions have been isolated and shown to beeffective in the transcription and translation of heterologous proteinsin the various hosts. Examples of these regions, methods of isolation,manner of manipulation, etc. are known in the art. Under appropriateexpression conditions, host cells can be used as a source ofrecombinantly produced semaphorins or analogs.

For the production of stably transformed cells and transgenic animals,nucleic acids encoding the disclosed semaphorins may be integrated intoa host genome by recombination events. For example, such a sequence canbe microinjected into a cell, and thereby effect homologousrecombination at the site of an endogenous gene, an analog or pseudogenethereof, or a sequence with substantial identity to ansemaphorin-encoding gene. Other recombination-based methods such asnonhomologous recombinations, deletion of endogenous gene by homologousrecombination, especially in pluripotent cells, etc., provide additionalapplications. Preferred transgenics and stable transformantsover-express the disclosed receptor gene and find use in drugdevelopment and as a disease model. Alternatively, knock-out cells andanimals find use in development and functional studies. Methods formaking transgenic animals, usually rodents, from ES cells or zygotes areknown to those skilled in the art.

The compositions and methods disclosed herein may be used to effect genetherapy. See, e.g. Zhu et al. (1993) Science 261, 209-211; Gutierrez etal. (1992) Lancet 339, 715-721. For example, cells are transfected withsemaphorin sequences operably linked to gene regulatory sequencescapable of effecting altered semaphorin expression or regulation. Tomodulate semaphorin translation, cells may be transfected withcomplementary antisense polynucleotides. For gene therapy involving thetransfusion of semaphorin transfected cells, administration will dependon a number of variables that are ascertained empirically. For example,the number of cells will vary depending on the stability of thetransfused cells. Transfusion media is typically a buffered salinesolution or other pharmacologically acceptable solution. Similarly theamount of other administered compositions, e.g. transfected nucleicacid, protein, etc., will depend on the manner of administration,purpose of the therapy, and the like.

The following examples are offered by way of illustration and not by wayof limitation.

EXAMPLES

I. Isolation and characterization of Grasshopper Semaphorin I (SEQ IDNOS:57 and 58) (previously referred to as Fasciclin IV)

In order to identify cell surface molecules that function in selectivefasciculation, a series of monoclonal antibody (MAb) screens wasconducted. The immunogen used for most of these screens was membranesfrom the longitudinal connectives (the collection of longitudinal axons)between adjacent segmental ganglia of the nervous system of the larvalgrasshopper. From these screens, MAb 3B11 and 8C6 were used to purifyand characterize two surface glycoproteins, fasciclin I and fasciclinII, see, Bastiani et al., 1987; the genes encoding both weresubsequently cloned, see, Snow et al. 1989, Zinn et al. 1988, andHarrelson and Goodman, 1988.

Another MAb isolated during these screens, MAb 6F8, was chosen for thepresent study because, just as with fasciclin I and fasciclin II, theantigen recognized by this MAb is expressed on a different butoverlapping subset of axon pathways in the developing CNS. The 6F8antigen appears to be localized on the outside of cell surfaces, asindicated by MAb binding when incubated both in live preparations, andin fixed preparations in which no detergents have been added. Becausethe 6F8 antigen is a surface glycoprotein expressed on a subset of axonfascicles (see below), we call it fasciclin IV.

Fasciclin IV expression begins early in embryonic development beforeaxonogenesis. At 29% of development, expression is seen on the surfaceof the midline mesectodermal cells and around 5-7 neuroblasts andassociated ectodermal cells per hemisegment. This expression isreminiscent of the mesectodermal and neuroblast-associated expressionobserved with both fasciclin I and fasciclin II; however, in each case,the pattern resolves into a different subset of neuroblasts andassociated ectodermal cells.

At 32% of development, shortly after the onset of axonogenesis in theCNS, fasciclin IV expression is seen on the surface of the axons andcell bodies of the three pairs of MP4, MP5, and MP6 midline progeny, thethree U motoneurons, and on several unidentified neurons in closeproximity to the U's. This is in contrast to fasciclin II, which at thisstage is expressed on the MP1 and dMP2 neurons, and fasciclin I, whichis expressed on the U neurons but not on any midline precursor progeny.

The expression of fasciclin IV on a subset of axon pathways is bestobserved around 40% of development, after the establishment of the firstlongitudinal and commissural axon pathways. At this stage, the proteinis expressed on two longitudinal axon fascicles, a subset of commissuralaxon fascicles, a tract extending anteriorly along the midline, and asubset of fascicles in the segmental nerve (SN) and intersegmental nerve(ISN) roots.

Specifically, fasciclin IV is expressed on the U fascicle, alongitudinal pathway (between adjacent segmental neuromeres) pioneeredin part by the U neurons, and on the A/P longitudinal fascicle (in partan extension of the U fascicle within each segmental neuromere). Inaddition, fasciclin IV is also expressed on a second narrower, medial,and more ventral longitudinal pathway. The U axons turn and exit the CNSas they pioneer the ISN; the U's and many other axons within the ISNexpress fasciclin IV. The continuation of the U fascicle posterior tothe ISN junction is also fasciclin IV-positive. The specificity offasciclin IV for distinct subsets of longitudinal pathways can be seenby comparing fasciclin IV and fasciclin II expression in the sameembryo; fasciclin IV is expressed on the U and A/P pathways whereasfasciclin II is expressed on the MP1 pathway.

The axons in the median fiber tract (MFT) also express fasciclin IV. TheMFT is pioneered by the three pairs of progeny of the midline precursorsMP4, MP5, and MP6. The MFT actually contains three separate fascicles.The axons of the two MP4 progeny pioneer the dorsal MFT fascicle andthen bifurcate at the posterior end of the anterior commissure; whereasthe axons of the two MP6 progeny pioneer the ventral MFT fascicle andthen bifurcate at the anterior end of the posterior commissure.Fasciclin IV is expressed on the cell bodies of the six MP4, MP5, andMP6 neurons, and on their growth cones and axons as they extendanteriorly in the MFT and bifurcate in one of the two commissures.However, this expression is regional in that once these axons bifurcateand begin to extend laterally across the longitudinal pathways andtowards the peripheral nerve roots, their expression of fasciclin IVgreatly decreases. Thus, fasciclin IV is a label for the axons in theMFT and their initial bifurcations in both the anterior and posteriorcommissures. It appears to be expressed on other commissural fasciclesas well. However, the commissural expression of fasciclin IV is distinctfrom the transient expression of fasciclin II along the posterior edgeof the posterior commissure, or the expression of fasciclin I on severaldifferent commissural axon fascicles in both the anterior and posteriorcommissure (Bastiani et al., 1987; Harrelson and Goodman, 1988).

Fasciclin IV is also expressed on a subset of motor axons exiting theCNS in the SN. The SN splits into two major branches, one anterior andthe other posterior, as it exits the CNS. Two large bundles ofmotoneuron axons in the anterior branch express fasciclin. IV at highlevels; one narrow bundle of motoneuron axons in the posterior branchexpresses the protein at much lower levels. Fasciclin IV is alsoexpressed on many of the axons in the ISN.

The CNS and nerve root expression patterns of fasciclin IV, fasciclin I,and fasciclin II at around 40% of embryonic development are summarizedin. Although there is some overlap in their patterns (e.g., bothfasciclin IV and fasciclin I label the U axons), these three surfaceglycoproteins label distinct subsets of axon pathways in the developingCNS.

Fasciclin IV is expressed on epithelial bands in the developing limb bud

Fasciclin IV is expressed on the developing limb bud epithelium incircumferential bands; at 34.5% of development these bands can belocalized with respect to constrictions in the epithelium that markpresumptive segment boundaries. In addition to a band just distal to thetrochanter/coxa segment boundary, bands are also found in the tibia,femur, coxa, and later in development a fifth band is found in thetarsus. Fasciclin IV is also expressed in the nascent chordotonal organin the dorsal aspect of the femur. The bands in the tibia, trochanter,and coxa completely encircle the limb. However, the femoral band isincomplete, containing a gap on the anterior epithelia of this segment.

The position of the Ti1 axon pathway with respect to these bands offasciclin IV-positive epithelia suggests a potential role for fasciclinIV in guiding the Ti1 growth cones. First, the band of fasciclin IVexpression in the trochanter, which is approximately three epithelialcell diameters in width when encountered by the Ti1 growth cones, is theaxial location where the growth cones reorient from proximal migrationto circumferential branch extension. The Tr1 cell, which marks thelocation of the turn, lies within this band, usually over the central orthe proximal cell tier. Secondly, although there is a more distalfasciclin IV expressing band in the femur, where a change in Ti1 growthis not observed, there exists a gap in this band such that fasciclin IVexpressing cells are not traversed by the Ti1 growth cones. The Ti1axons also may encounter a fasciclin IV expressing region within thecoxa, where interactions between the growth cones, the epithelial cells,and the Cx1 guidepost cells have not yet been investigated.

In addition to its expression over the surface of bands of epithelialcells, fasciclin IV protein, as visualized with MAb 6F8, is also foundon the basal surface of these cells in a punctate pattern. This punctatestaining is not an artifact of the HRP immunocytochemistry sincefluorescent visualization of MAb 6F8 is also punctate. The non-neuronalexpression of fasciclin IV is not restricted to limb buds.Circumferential epithelial bands of fasciclin IV expression are alsoseen on subesophageal mandibular structures and on the developingantennae.

MAb directed against fasciclin IV can alter the formation of the Ti1axon pathway in the limb bud

The expression of fasciclin IV on an epithelial band at a key choicepoint in the formation of the Ti1 axon pathway led us to ask whetherthis protein is involved in growth cone guidance at this location. Toanswer this question, we cultured embryos, or epithelial fillets (e. g.,O'Connor et al., 1990), during the 5% of development necessary fornormal pathway formation, either in the presence or absence of MAb 6F8or 6F8 Fab fragments. Under the culture conditions used for theseexperiments, defective Ti1 pathways are observed in 14% of limbs (Changet al., 1992); this defines the baseline of abnormalities observed usingthese conditions. For controls we used other MAbs and their Fabfragments that either bind to the surfaces of these neurons andepithelial cells (MAb 3B11 against the surface protein fasciclin I) ordo not (MAb 4D9 against the nuclear protein engrailed; Patel et al.,1989). To assess the impact of MAb 6F8 on Ti1 pathway formation, wecompared the percentage of aberrant pathways observed followingtreatment with MAb 6F8 to that observed with MAbs 3B11 and 4D9. Ourcultures began at 32% of development when the Ti1 growth cones have notyet reached the epithelium just distal to the trochanter/coxa boundaryand therefore have not encountered epithelial cells expressing fasciclinIV. Following approximately 30 hours in culture (˜4% of development),embryos were fixed and immunostained with antibodies to HRP in order tovisualize the Ti1 axons and other neurons in the limb bud. Criteria forscoring the Ti1 pathway, and the definition of "aberrant", are describedin detail in the Experimental Procedures.

Although MAb 6F8 does not arrest pathway formation, several types ofdistinctive, abnormal pathways are observed. These defects generallybegin where growth cones first contact the fasciclin IV expressing cellsin the trochanter. Normally, the Ti1 neurons each have a single axon,and the axons of the two cells are fasciculated in that portion of thepathway within the trochanter. Following treatment with MAb 6F8,multiple long axon branches are observed within, and proximal to, thetrochanter. Two major classes of pathways are taken by these branches;in 36% of aberrant limbs, multiple, long axon branches extend ventrallyin the region distal to the Cx1 cells which contains the band offasciclin IV expressing epithelial cells. In the ventral region of thetrochanter, these branches often independently turn proximally tocontact the Cx1 cells, and thus complete the pathway in this region.

In the second major class of pathway defect, seen in 47% of aberrantlimbs, axon branches leave the trochanter at abnormal, dorsal locations,and extend proximally across the trochanter/coxa boundary. These axonsthen veer ventrally, often contacting the Cx1 neurons. The remaining 17%of defects include defasciculation distal to the trochanter, axonbranches that fail to turn proximally in the ventral trochanter andcontinue into the posterior compartment of the limb, and axon brancheswhich cross the trochanter/coxa boundary and continue to extendproximally without a ventral turn.

When cultured in the presence of MAb 6F8, 43% of limbs exhibitedmalformed Ti1 pathways (n=381) as compared to 11% with MAb 3B11 (n=230)and 5% with MAb 4D9 (n=20). These percentages are pooled from treatmentswith MAbs concentrated from hybridoma supernatant, IgGs isolated fromthese supernatants, and Fab fragments isolated from these IgGpreparations (see Experimental Procedures). The frequency of malformedTi1 pathways and the types of defects observed showed no significantvariation regardless of the method of antibody preparation or type ofantibody used. Since Fabs show similar results as IgGs, the effects ofMAb 6F8 are not due to cross linking by the bivalent IgG.

In summary, following treatment with MAb 6F8, the Ti1 pathway typicallyexhibits abnormal morphology beginning just distal to the trochanter andat the site of fasciclin IV expression. The two most common types of Ti1pathway defects described above occur in 36% of experimental limbs(treated with MAb 6F8), but are seen in only 4% of control limbs(treated with MAbs 3 B11 and 4D9).

Fasciclin IV cDNAs encode a novel integral membrane protein

Grasshopper fasciclin IV was purified by passing crude embryonicgrasshopper lysates over a MAb 6F8 column. After affinity purification,the protein was eluted, precipitated, denatured, modified at cysteines,and digested with either trypsin or Lys-C. Individual peptides wereresolved by reverse phase HPLC and microsequenced using standardmethods.

The amino acid sequences derived from these proteolytic fragments wereused to generate oligonucleotide probes for PCR experiments, resultingin products that were used to isolate cDNA clones from the Zinnembryonic grasshopper cDNA library (Snow et al., 1988). Sequenceanalysis of these cDNAs reveals a single open reading frame (ORF)encoding a protein with two potential hydrophobic stretches of aminoacids: an amino-terminal signal sequence of 20 residues and (beginningat amino acid 627) a potential transmembrane domain of 25 amino acids.Thus, the deduced protein has an extracellular domain of 605 aminoacids, a transmembrane domain, and a cytoplasmic domain of 78 aminoacids. The calculated molecular mass of the mature fasciclin IV proteinis 80 kd and is confirmed by Western blot analysis of the affinitypurified and endogenous protein as described below. The extracellulardomain of the protein includes 16 cysteine residues that fall into threeloose clusters but do not constitute a repeated domain and are notsimilar to other known motifs with cysteine repeats. There are also sixpotential sites for N-linked glycosylation in the extracellular domain.Treatment of affinity purified fasciclin IV with N-Glycanasedemonstrates that fasciclin IV does indeed contain N-linkedoligosaccharides. Fasciclin IV shows no sequence similarity whencompared with other proteins in the PIR data base using BLASTP (Altschulet al., 1990), and is therefore a novel type I integral membraneprotein.

A polyclonal antiserum directed against the cytoplasmic domain of theprotein encoded by the fasciclin IV cDNA was used to stain grasshopperembryos at 40% of development. The observed staining pattern wasidentical to that seen with MAb 6F8. On Western blots, this antiserumrecognizes the protein we affinity purified using MAb 6F8 and thensubjected to microsequence analysis. Additionally, the polyclonal serumrecognizes a protein of similar molecular mass from grasshopperembryonic membranes. Taken together these data indicate that thesequence we have obtained is indeed fasciclin IV.

Four other cell surface proteins that label subsets of axon pathways inthe insect nervous system (fasciclin I, fasciclin II, fasciclin m, andneuroglian) are capable of mediating homophilic cell adhesion whentransfected into S2 cells in vitro (Snow et al., 1989; Elkins et al.,1990b; Grenningloh et al., 1990). To ask whether fasciclin IV canfunction as a homophilic cell adhesion molecule, the fasciclin IV cDNAwith the complete ORF was placed under the control of the induciblemetallothionein promoter (Bunch et al., 1988), transfected into S2cells, and assayed for its ability to promote adhesion in normallynon-adhesive S2 cells. Following induction with copper, fasciclin IV wassynthesized in these S2 cells as shown by Western blot analysis and cellsurface staining of induced S2 cells with the polyclonal antiserumdescribed above.

We observed no evidence for aggregation upon induction of fasciclin IVexpression, thus suggesting that, in contrast to the other fourproteins, fasciclin IV does not function as a homophilic cell adhesionmolecule. Alternatively, fasciclin IV-mediated aggregation might requiresome further posttranslational modification, or co-factor, not suppliedby the S2 cells, but clearly this protein acts differently in the S2cell assay than the other four axonal glycoproteins previously tested.This is consistent with the pattern of fasciclin IV expression in theembryonic limb since only the epithelial cells and not the Ti1 growthcones express fasciclin IV, and yet antibody blocking experimentsindicate that fasciclin IV functions in the epithelial guidance of thesegrowth cones. Such results suggest that fasciclin IV functions in aheterophilic adhesion or signaling system.

Discussion

Fasciclin IV is expressed on groups of axons that fasciculate in theCNS, suggesting that, much like other insect axonal glycoproteins, itfunctions as a homophilic cell adhesion molecule binding these axonstogether. Yet, in the limb bud, fasciclin IV is expressed on a band ofepithelium but not on the growth cones that reorient along this band,suggesting a heterophilic function. That fasciclin IV functions in aheterophilic rather than homophilic fashion is supported by the lack ofhomophilic adhesion in S2 cell aggregation assays. In contrast,fasciclin I, fasciclin II, fasciclin III, and neuroglian all canfunction as homophilic cell adhesion molecules (Snow et al., 1989;Elkins et al., 1990b; Grenningloh et al., 1990).

cDNA sequence analysis indicates that fasciclin IV is an integralmembrane protein with a novel sequence not related to any protein in thepresent data base. Thus, fasciclin IV represents a new type of proteinthat functions in the epithelial guidance of pioneer growth cones in thedeveloping limb bud. Given its expression on a subset of axon pathwaysin the developing CNS, fasciclin IV functions in the guidance of CNSgrowth cones as well.

The results from the MAb blocking experiments illuminate several issuesin Ti1 growth cone guidance and axon morphogenesis in the limb. First,the most striking change in growth cone behavior in the limb is thecessation of proximal growth and initiation of circumferential extensionof processes upon encountering the trochanter/coxa boundary region(Bentley and Caudy, 1983; Caudy and Bentley, 1987). This could bebecause the band of epithelial cells within the trochanter promotescircumferential growth, or because the cells comprising thetrochanter/coxa boundary and the region just proximal to it arenon-permissive or aversive for growth cone migration, or both. Theextension of many axon branches across the trochanter/coxa boundaryfollowing treatment with MAb 6F8 suggests that the trochanter/coxaboundary cells, which do not express fasciclin IV, are not aversive ornon-permissive. Thus the change in behavior at the boundary appears tobe due to the ability of fasciclin IV expressing epithelial cells topromote circumferential extension of processes from the Ti1 growthcones.

Secondly, treatment with MAb 6F8 results in frequent defasciculation ofthe axons of the two Ti1 neurons, and also formation of abnormalmultiple axon branches, within the trochanter over fasciclinIV-expressing epithelial cells. Previous studies have shown thattreatment with antibodies against ligands expressed on non-neuralsubstrates (Landmesser et al., 1988), or putative competitive inhibitorsof substrate ligands (Wang and Denburg, 1992) can promotedefasciculation and increased axonal branching. Our results suggest thatTi1 axon:axon fasciculation and axon branching also are stronglyinfluenced by interactions with substrate ligands, and that fasciclin IVappears to be a component of this interaction within the trochanter.

Thirdly, despite the effects of MAb 6F8 on axon branching, and oncrossing the trochanter/coxa boundary, there remains a pronouncedtendency for branches to grow ventrally both within the trochanter andwithin the distal region of the coxa. Consequently, all signals whichcan promote ventral migration of the growth cones have not been blockedby MAb 6F8 treatment. Antibody treatment may have a threshold effect inwhich ventral growth directing properties of fasciclin IV are morerobust, and less incapacitated by treatment, than other features;alternatively, guidance information promoting ventral migration may beindependent of fasciclin IV. Time lapse video experiments to determinehow the abnormal pathways we observe actually form can resolve theseissues.

These results demonstrate that fasciclin IV functions as a guidance cuefor the Ti1 growth cones just distal to the trochanter/coxa boundary, isrequired for these growth cones to stop proximal growth and spreadcircumferentially, and that the function of fasciclin IV in Ti1 pathwayformation result from interactions between a receptor/ligand on the Ti1growth cones and fasciclin IV on the surface of the band of epithelialcells results in changes in growth cone morphology and subsequentreorientation. Fasciclin IV appears to elicit this change in growth conemorphology and orientation via regulation of adhesion, a signaltransduction function, or a combination of the two.

Experimental Procedures

Enmunocytochemistry

Grasshopper embryos were obtained from a colony maintained at the U. C.Berkeley and staged by percentage of total embryonic development(Bentley et al., 1979). Embryos were dissected in PBS, fixed for 40 minin PEM-FA 0.1M PIPES (pH6.95), 2.0 mM EGTA, 1.0 mM MgSO₄, 3.7%formaldehyde!, washed for 1 hr with three changes in PBT (1×PBS, 0.5%Triton X-100, 0.2% BSA), blocked for 30 min in PBT with 5% normal goatserum, and incubated overnight at 4° C. in primary antibody. PBSap(1×PBS, 0.1% Saponin, o.2% BSA) was used in place of PBT with MAb 8G7.Antibody dilutions were as follows: MAb 6F8 1:1, polyclonal antiseradirected against a fasciclin IV bacterial fusion protein (#98-3) 1:400;MAb 8G7 1:4; MAb 8C6 1:1. The embryos were washed for one hour in PBTwith three changes, blocked for 30 min, and incubated in secondaryantibody for at least 2 hr at room temperature. The secondary antibodieswere HRP-conjugated goat anti-mouse and anti-rat IgG (JacksonImmunoresearch Lab), and were diluted 1:300. Embryos were washed in PBTfor one hour with three changes and then reacted in 0.5%diaminobenzidine (DAB) in PBT. The reaction was so with several washesin PBS and the embryos were cleared in a glycerol series (50%, 70%,90%), mounted and viewed under Nomarski or bright field optics. Fordouble-labelled preparations the first HRP reaction was done in PBTcontaining 0.06% NiCl, followed by washing, blocking, and incubationovernight in the second primary antibody. The second antibody wasvisualized with a DAB reaction as described above. Embryos cultured inthe presence of monoclonal antibodies were fixed and incubated overnightin goat anti-HRP (Jackson Immunoresearch Labs) conjugated to RITC(Molecular Probes), washed for one hour in PBT with three changes,mounted in 90% glycerol, 2.5% DABCO (Polysciences), and viewed underepifluorescence. S2 cells were stained with polyclonal sera #98-3diluted 1:400 and processed as described previously (Snow et al., 1989).

Monoclonal Antibody Blocking Experiments

In order to test for functional blocking, monoclonal antibody reagentswere prepared as follows. Hybridoma supernatant was brought to 20% withH₂ O-saturated (NH₄)₂, incubated in ice 1 hr, and spun at 15,000 g at 4°C. for 20 min. The supernatant was brought to 56% with H₂ O-saturated(NH₄)₂, incubated overnight at 4° C., spun as above. The pellet wasresuspended in PBS using approximately 1/40 volume of the originalhybridoma supernatant (often remaining a slurry) and dialyzed against1×PBS overnight at 4° C. with two changes. This reagent is referred toas "concentrated hybridoma supernatant." Purified IgG was obtained byusing Immunopure Plus Immobilized Protein A IgG Purification Kit(Pierce) to isolate IgG from the concentrated hybridoma supernatant. Fabfragments were obtained using the ImmunoPure Fab Preparation Kit(Pierce) from the previously isolated IgGs. For blocking experimentseach reagent was diluted into freshly made supplemented RPMI culturemedia (O'Connor et al., 1990) and dialyzed overnight at 4° C against 10volumes of the same culture media. Dilutions were as follows:concentrated hybridoma supernatant 1:4; purified IgG 150 mg/ml; Fab 75mg/ml.

Embryos for culture experiments were carefully staged to between 31 and32% of development. As embryos in each clutch typically differ by lessthat 1% of embryonic development from each other, the growth cones ofthe Ti1 neurons at the beginning of the culture period were locatedapproximately in the mid-femur, well distal to the trochanter/coxasegment boundary. From each clutch at least two limbs were filleted andthe Ti1 neurons labelled with the lipophillic dye Di I (MolecularProbes) as described (O'Connor et al., 1990) in order to confirm theprecise location of the Ti1 growth cones. Prior to culturing, embryoswere sterilized and dissected (Chang et al., 1992). The entire amnionand dorsal membrane was removed from the embryo to insure access of thereagents during culturing. Embryos were randomly divided into groups andcultured in one of the blocking reagents described above. Cultures wereincubated with occasional agitation at 30° C. for 30 hrs. At the end ofthe culture period embryos were fixed and processed for analysis asdescribed above in immunocytochemistry.

For each culture experiment, the scoring of the Ti1 pathway in each limbwas confirmed independently by a second observer. There was nostatistically significant variation between the two observers. Limbsfrom MAb cultured embryos were compared to representative normal limbsfrom non-MAb cultured embryos and were scored as abnormal if any majordeviation from the normal Ti1 pathway was observed. The Ti1 pathway wasscored as abnormal for one or more of the following observedcharacteristics: (1) defasciculation for a minimum distance ofapproximately 25 mm anywhere along the pathway, (2) multiple axonbranches that extended ventrally within the trochanter, (3) presence ofone or more axon branches that crossed the trochanter/coxa boundarydorsal to the Cx1 cells, but then turned ventrally in the coxa andcontacted the Cx1 cells, (4) the presence of axon branches that crossedthe trochanter/coxa segment boundary, did not turn ventrally, butcontinued proximally toward the CNS, and (5) failure of ventrallyextended axons within the trochanter to contact and reorient proximallyto the Cx1 cells. For each MAb tested, the data are presented as apercentage of the abnormal Ti1 pathways observed.

Protein Affinity Purification and Microsequencing

Grasshopper fasciclin IV was purified by passing crude embryonicgrasshopper lysate (Bastiani et al., 1987) over an Affi-Gel 15 column(Rio Rad) conjugated with the monoclonal antibody 6F8. Protein waseluted with 50 mM DEA (H 11.5), 0.1% Lauryldimethylamine oxide (Cal BioChem), and 1 mM EDTA. Protein was then precipitated, denatured, modifiedat cysteines, and digest with either trypsin or Lys-C(Boehringer-Mannheim). Individual peptides were resolved by RP-HPLC andmicrosequenced (Applied Biosystems 4771 Microsequencer) using standardchemistry.

PCR Methods

DNA complementary to poly(A)+ RNA from 45%-50% grasshopper embryos wasprepared (Sambrook et al., 1989). PCR was performed using Perkin ElmerTaq polymerase (Saiki et al., 1988), and partially degenerate (based ongrasshopper codon bias) oligonucleotides in both orientationscorresponding to a portion of the protein sequence of several fasciclinIV peptides as determined by microsequencing. These oligonucleotideswere designed so as not to include all of the peptide-derived DNAsequence, leaving a remaining 9-12 base pairs that could be used toconfirm the correct identity of amplified products. All possiblecombinations of these sequences were tried. 40 cycles were performed,the parameters of each cycle as follows: 96° for one min; a sequentiallydecreasing annealing temperature (2° C./cycle, starting at 65° C. andending at 55° C. for remaining 35 cycles) for 1 min; and at 72° C. forone min. Reaction products were cloned into the Sma site of M13 mp10 andsequenced. Two products, 1074 bp and 288 bp in length, contained DNA 3'to the oligonucleotide sequences encoded the additional amino acidsequence of the fasciclin IV peptide from which the oligonuceotides werederived. These two fragments have one end in common, and theoligonucleotides used to amplify them correspond to the amino acidsequences -Met-Tyr-Val-Gln-Phe-Gly-Glu-Glu-, and-Met-Asp-Glu-Ala-Val-Pro-Ala-Phe- (fasciclin IV residue 29-386), and-His-Thr-Leu-Met-Asp-Glu-Ala-, and -Lys-Asn-Tyr-Val-Val-Arg-Met-Asp-Glu(fasciclin IV residue 376-472).

cDNA Isolation and Sequence Analysis

Both PCR products were used to screen 1×10⁶ clones from a grasshopperembryonic cDNA library (Snow et al., 1988). 21 clones that hybridized toboth fragments were recovered, and one 2600 bp clone was sequenced usingthe dideoxy chain termination method (Sanger et al., 1977) and Sequenase(US Biochemical Corp.). Templates were made from M13 mp10 vectorscontaining inserts generated by sonication of plasmid clones. One cDNAwas completely sequenced on both strands using Oligonucleotides anddouble strand sequencing of plasmid DNA (Sambrook et al., 1989) to fillgaps. Two additional cDNAs were analyzed by double strand sequencing toobtain the 3' 402 bp of the transcript. All three cDNAs were used toconstruct a plasmid containing the entire transcript. The completetranscript sequence is 2860 bp in length with 452 bp of 5' and 217 bp of3' untranslated sequences containing stop codons in all reading frames.The predicted protein sequence was analyzed using the FASTDB and BLASTPprograms (Intelligenetics). The fasciclin IV ORF unambiguously contains10 of the 11 peptide sequences determined by microsequencing thefasciclin IV trypsin and Lys-C peptides.

Generation of Polyclonal Antibodies From Bacterial Fusion Proteins

Bacterial trpE fusion proteins were constructed using pATH (Koerner etal., 1991) vectors, three restriction fragments encoding extracellularsequences, and one fragment (770 bp HindII/Eco R1, which includes aminoacids 476-730) encoding both extracellular and intracellular sequences(designed #98-3). Fusion proteins were isolated by making an extract ofpurified inclusion bodies (Spindler et al., 1984), and rats wereimmunized with ˜70 mg of protein emulsified in RIBI adjuvant (ImmunochemReserch). Rats were injected at two week intervals and serum wascollected 7 days following each injection. Sera were testedhistologically on grasshopper embryos at 45% of development. Construct#98-3 showed a strong response and exhibited a staining patternidentical to that of MAb 6F8. Two of the extracellular constructsresponded weakly but also showed the fasciclin IV staining pattern. Allpre-immune sera failed to stain grasshopper embryos.

S2 Cell Transfections, Aggregation Assays, and Western Analysis

A restriction fragment containing the full length fasciclin IV cDNA wascloned into pRmHa-3 (Bunch et al, 1988) and co-transformed intoDrosophila S2 cells (Schneider, 1972) with the plasmid pPC4 (Jokerst etal., 1989), which confers a-amanitin resistance. S2 cells weretransformed using the Lipofectin Reagent and recommended protocol (BRL)with nor modifications. All other S2 cell manipulations are essentiallyas described (Snow et al., 1989), including adhesion assays. FasciclinIV expression in transformed cell lines was induced for adhesion assaysand histology by adding CuSo₄ to 0.7 mM and incubating for at least 48hrs. Northern analysis confirmed transcription of fasciclin TV andsurface-associated staining of the S2 cells with polyclonal serum #98-3strongly suggests fasciclin IV is being transported to the cell surface.Preparation of membranes from S2 cells and from grasshopper embryos,PAGE, and Western blot were performed as previously described (Elkins etal., 1990b) except that signal was detected using the enhancedchemiluminescence immunodetection system kit (Amersham). Amount ofprotein per lane in each sample loaded: fasciclin IV protein, ˜5 ng; S2cell membranes, 40 mg; grasshopper membranes 80 mg. Amounts of proteinloaded were verified by Ponceau S staining of the blot prior toincubation with the antibody.

References cited in Example I

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Genbank Accession Number

The accession number for the sequence reported in this paper is L00709.

II. Isolation and characterization of Tribolium (SEQ ID NOS:63 and 64)and Drosophila (SEQ ID NOS:59 and 60) Semaphorin I. DrosophilaSemaphorin II. (SEQ ID NOS:61 and 62) Human Semaphorin III (SEQ IDNOS:53 and 54) and Vaccinia Virus Semaphorin IV (SEQ ID NOS:55 and 56)and Variola Major (smallpox) Virus Semaphorin V (SEQ ID NOS:67 and 68).

We used our G-Semaphorin I cDNA in standard low stringency screeningmethods (of both cDNA and genomic libraries) in an attempt to isolate apotential Semaphorin I homologue from Drosophila. We were unsuccessfulin these screens. Since the sequence was novel and shared no similarityto anything else in the data base, we then attempted to see if we couldidentify a Semaphorin I homologue in other, more closely relatedinsects. If possible, we would then compare these sequences to find themost conserved regions, and then to use probes (i.e., oligonucleotideprimers for PCR) based on these conserved regions to find a Drosophilahomologue.

In the process, we used the G-Semaphorin I cDNA in low stringencyscreens to clone Semaphorin I cDNAs from libraries made from locustLocusta migratoria embryonic RNA and from a cDNA embryonic library fromthe cricket Acheta domestica. We used PCR to clone genomic fragmentsfrom genomic DNA in the beetle Tribolium, and from the moth Manduca. Wethen used the Tribolium genomic DNA fragment to isolate cDNA clones andultimately sequenced the complete ORF for the Tribolium cDNA.

In the meantime, we used the partial Tribolium and Manduca sequences incombination with the complete grasshopper sequence to identify conservedregions that allowed us to design primers for PCR in an attempt to clonea Drosophila Semaphorin I homologue. Several pairs of primers generatedseveral different bands, which were subcloned and sequenced and severalof the bands gave partial sequences of the Drosophila Semaphorinhomologue. One of the bands gave a partial sequence of what was clearlya different, more divergent gene, which we call D-Semaphorin II.

Based on the sequence of PCR products, we knew we had identified twodifferent Drosophila genes, one of which appeared to be the Semaphorin Ihomologue, and the other a second related gene. The complete ORFsequence of the D-Semaphorin I homologue revealed an overall structureidentical to G-Semaphorin I: a signal sequence, an extracellular domainof around 550 amino acids containing 16 cysteines, a transmembranedomain of 25 amino acids, and a cytoplasmic domain of 117 amino acids.When we had finished the sequence for D-Semaphorin II, we were able tobegin to run homology searches in the data base, which revealed some ofits structural features further described herein. The Semaphorin IIsequence revealed a different structure: a signal sequence of 16 aminoacids, a ˜525 amino acid domain containing 16 cysteines, with a singleimmunoglobulin (Ig) domain of 66 amino acids, followed by a short uniqueregion of 73 amino acids. There is no evidence for either atransmembrane domain or a potential phospholipid linkage in theC-terminus of this protein. Thus, it appears that the D-Semaphorin IIprotein is secreted from the cells that produce it. The grasshopper,Tribolium, and Drosophila Semaphorin I cDNA sequences, as well as thesequence of the D-Semaphorin II cDNA, are shown herein. In addition, weused this same technique to identify Semaphorin I genes in a moth,Manduca sexta, a locust, Locusta migratoria, and a cricket, Achetadomestica.

With this large family of insect Semaphorin genes, we identified anumber of good stretches of the right amino acids (with the leastdegeneracy based on their codons) with strong homology for designingprimers for PCR to look for human genes. We designed a set ofoligonucleotide primers, and plated out several human cDNA libraries: afetal brain library (Stratagene), and an adult hippocampus library. Weultimately obtained a human cDNA PCR bands of the right size that didnot autoprime and thus were good candidates to be bonafideSemaphorin-like cDNAs from humans. These bands were purified, subcloned,and sequenced.

Whole-mount in situ hybridization experiments showed that D-Semaphorin Iand II are expressed by different subsets of neurons in the embryonicCNS. D-Semaphorin I is expressed by certain cells along the midline aswell as by other neurons, whereas D-Semaphorin II is not expressed atthe midline, but is expressed by a different subset of neurons. Inaddition, D-Semaphorin II is expressed by a subset of muscles prior toand during the period of innervation by specific motoneuron. On thepolytene chromosomes, the D-Semaphorin I gene maps to(gene-band-chromosome) 29E1-22L and that of D-Semaphorin II to53C9-102R. We have identified loss of function mutations in theD-Semaphorin I gene and a pair of P-element transposon insertions in theD-Semaphorin II gene which appear to cause severe phenotypes.

When we lined up the G-Semaphorin I, T-Semaphorin I, D-Semaphorin I, andD-Semaphorin II sequences and ran the sequences through a sequence database in search of other sequences with significant similarity, wediscovered a curious finding: these Semaphorins share sequencesimilarity with the A39R open reading frame (ORF) from Vaccinia virusand the A43R ORF from Variola Major (smallpox) virus and we discoveredthat the amino acids shared with the virus ORF were in the same regionswhere the insect proteins shared their greatest similarity. The viralORF began with a putative signal sequence, continued for several hundredamino acids with sequence similarity to the Semaphorin genes, and thenended without any membrane linkage signal (suggesting that the proteinas made by the infected cell would likely be secreted).

We reasoned that the virus semaphorins were appropriated host proteinsadvantageously exploited by the viruses, which would have hostcounterparts that most likely function in the immune system to inhibitor decrease an immune response, just as in the nervous system theyappear to function by inhibiting growth cone extension. Analogous tosituations where viruses are thought to encode a secreted form of a hostcellular receptor, here the virus may cause the infected cell to make alot of the secreted ligand to mimic an inhibitory signal and thus helpdecrease the immune response.

III. Isolation and characterization of Murine CNS Semaphorin IIIReceptor using Epitope Tagged Human Semaphorin III (hsIII)

mRNA was isolated from murine fetal brain tissue and used to construct acDNA library in a mammalian expression vector, pCMX, essentially as inDavis et al. (1991) Science 253, 59.

The transfection and screening procedure is modified from Lin et al(1992) Cell 68, 775. COS cells grown on glass slide flaskettes aretransfected with pools of the cDNA clones, allowed to bindradioiodinated hSIII truncated at the C-terminus end of the semaphorindomain. In parallel, similarly treated COS cells are allowed to bindunlabelled human semaphorin III truncated at the C-terminus end of thesemaphorin domain and there joined to a 10-amino acid extension derivedfrom the human c-myc proto-oncogene product. This modified hSIII allowsthe identification of hSIII receptors with the use of the tagged ligandas a bridge between the receptor and a murine monoclonal antibody whichis specific for an epitope in the c-myc tag. Accordingly, after bindingunlabelled hSIII the cells are exposed to the monoclonal which may belabeled directly or subsequently decorated with a secondary anti-mouselabeled antibody for enhanced signal amplification.

Cells are then fixed and screened using dark-field microscopyessentially as in Lin et al. (supra). Positive clones are identified andsequence analysis of murine CNS Semphorin III receptor cDNA clones bythe dideoxy chain termination method is used to construct full-lengthreceptor coding sequences.

It is evident from the above results that one can use the methods andcompositions disclosed herein for making and identifying diagnosticprobes and therapeutic drugs. It will also be clear to one skilled inthe art from a reading of this disclosure that advantage can be taken toeffect alterations of semaphorin responsiveness in a host.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. Although the foregoing invention has beendescribed in some detail by way of illustration and example for purposesof clarity of understanding, it will be readily apparent to those ofordinary skill in the art in light of the teachings of this inventionthat certain changes and modifications may be made thereto withoutdeparting from the spirit or scope of the appended claims.

                                      TABLE 1                                     __________________________________________________________________________    Deduced amino-acid sequence of semaphorin gene family.                        Approximate position of enumerated peptide classes are indicated by           parenthetical (a) through                                                     (o); semaphorin domains are bounded by arrows; G: grasshopper semaphorin      I (SEQ ID NO:58), T:                                                          Tribolium semaphorin I (SEQ ID NO:64), D1: Drosophila semaphorin I (SEQ       ID NO:60), D2:                                                                Drosophila semaphorin II (SEQ ID NO:62), H3: Human semaphorin I (SEQ ID       NO:54), V4:                                                                   Vaccinia virus semaphorin IV (SEQ ID NO:56), V5: Variola virus (human         small pox) semaphorin                                                         IV (SEQ ID NO:66); small case residues: conserved residues; underline:        signal sequence; solid bar:                                                   transmembrane domain; double dashes: immunoglobulin domain.                   __________________________________________________________________________     ##STR1##                                                                      ##STR2##                                                                      ##STR3##                                                                      ##STR4##                                                                      ##STR5##                                                                      ##STR6##                                                                      ##STR7##                                                                      ##STR8##                                                                      ##STR9##                                                                      ##STR10##                                                                     ##STR11##                                                                     ##STR12##                                                                     ##STR13##                                                                     ##STR14##                                                                     ##STR15##                                                                     ##STR16##                                                                     ##STR17##                                                                    H3RPGHTPGNSNKHLQENKKGRNRRTHEFERAPRSV*                                         __________________________________________________________________________

    __________________________________________________________________________    SEQUENCE LISTING                                                              (1) GENERAL INFORMATION:                                                      (iii) NUMBER OF SEQUENCES: 100                                                (2) INFORMATION FOR SEQ ID NO:1:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..6                                                            (D) OTHER INFORMATION: /label=SEQ01                                           /note= "Xaa denotes D or E at residue #1; Q,K,R,A                             or N at residue #3; and Y,F or V at residue #5"                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                                       XaaCysXaaAsnXaaIle                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:2:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..6                                                            (D) OTHER INFORMATION: /label=SEQ02                                           /note= "Xaa denotes Q,K,R,A or N at residue #2;                               Y,F or V at residue #4; and R,K,Q or T at residue                             #6"                                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                                       CysXaaAsnXaaIleXaa                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:3:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ03                                           /note= "Xaa denotes N or G at residue #4; A,S or N                            at residue #5; Y,F,H or G at residue #6; and                                  K,R,H,N or Q at residue #7"                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                                       CysGlyThrXaaXaaXaaXaa                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:4:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ04                                           /note= "Xaa denotes N or G at residue #4; and A,S                             or N at residue #5"                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                                       CysGlyThrXaaXaaXaaXaaPro                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:5:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..10                                                           (D) OTHER INFORMATION: /label=SEQ05                                           /note= "Xaa denotes N or G at residue #4; and C or                            D at residue #10"                                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                                       CysGlyThrXaaXaaXaaXaaProXaaXaa                                                1510                                                                          (2) INFORMATION FOR SEQ ID NO:6:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..13                                                           (D) OTHER INFORMATION: /label=SEQ06                                           /note= "Xaa denotes C or D at residue #10; and Y                              or I at residue #13"                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                                       CysGlyThrXaaXaaXaaXaaProXaaXaaXaaXaaXaa                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO:7:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ07                                           /note= "Xaa denotes R,I,Q or V at residue #1; G or                            A at residue #2; L,V or K at residue #3; C or S at                            residue #4; F or Y at residue #6; and D or N at                               residue #7"                                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                                       XaaXaaXaaXaaProXaaXaa                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:8:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ08                                           /note= "Xaa denotes C or S at residue #1; F or Y                              at residue #3; D or N at residue #4; D,E,R or K at                            residue #6; and H,L or D at residue #7"                                       (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                                       XaaProXaaXaaProXaaXaa                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:9:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..9                                                            (D) OTHER INFORMATION: /label=SEQ09                                           /note= "Xaa denotes G or A at residue #3; C or S                              at residue #5; and D or N at residue #8"                                      (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:                                       GlyXaaXaaXaaXaaProTyrXaaPro                                                   15                                                                            (2) INFORMATION FOR SEQ ID NO:10:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ10                                           /note= "Xaa denotes F or Y at residue #2; G or A                              at residue #4; and V,N or A at residue #6"                                    (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:                                      LeuXaaSerXaaThrXaaAla                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:11:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..9                                                            (D) OTHER INFORMATION: /label=SEQ11                                           /note= "Xaa denotes F or Y at residue #2; D or E                              at residue #8; and F or Y at residue #9"                                      (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:                                      LeuXaaSerXaaThrXaaAlaXaaXaa                                                   15                                                                            (2) INFORMATION FOR SEQ ID NO:12:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ12                                           /note= "Xaa denotes F or Y at residue #1; G or A                              at residue #3; V,N or A at residue #5; D or E at                              residue #7; and F or Y at residue #8"                                         (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:                                      XaaSerXaaThrXaaAlaXaaXaa                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:13:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ13                                           /note= "Xaa denotes N or D at residue #2; and A or                            K at residue #3"                                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:                                      LeuXaaXaaProAsnPheVal                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:14:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 5 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:                                      PhePhePheArgGlu                                                               15                                                                            (2) INFORMATION FOR SEQ ID NO:15:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..6                                                            (D) OTHER INFORMATION: /label=SEQ15                                           /note= "Xaa denotes F or Y at residue #3; and T or                            N at residue #6"                                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:                                      PhePheXaaArgGluXaa                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:16:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..6                                                            (D) OTHER INFORMATION: /label=SEQ16                                           /note= "Xaa denotes T or N at residue #5"                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:                                      PhePheArgGluXaaAla                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:17:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..6                                                            (D) OTHER INFORMATION: /label=SEQ17                                           /note= "Xaa denotes F or Y at residue #2; and T or                            N at residue #5"                                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:                                      PheXaaArgGluXaaAla                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:18:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..6                                                            (D) OTHER INFORMATION: /label=SEQ18                                           /note= "Xaa denotes F or Y at residue #4"                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:                                      TyrPhePheXaaArgGlu                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:19:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..6                                                            (D) OTHER INFORMATION: /label=SEQ19                                           /note= "Xaa denotes F or Y at residue #1; and F or                            Y at residue #4"                                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:                                      XaaPhePheXaaArgGlu                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:20:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ20                                           /note= "Xaa denotes F or Y at residue #1; F or Y                              at residue #2; F or Y at residue #3; and T or N at                            residue #6"                                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:                                      XaaXaaXaaArgGluXaaAla                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:21:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ21                                           /note= "Xaa denotes I or V at residue #1; F or Y                              at residue #2; F or Y at residue #4; and F or Y at                            residue #5"                                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:                                      XaaXaaPheXaaXaaArgGlu                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:22:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ22                                           /note= "Xaa denotes K,F or Y at residue #2; F or Y                            at residue #4; F,Y,I or L at residue #5; F,Y,I or                             L at residue #6; and F or Y at residue #7"                                    (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:                                      AspXaaValXaaXaaXaaXaa                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:23:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ23                                           /note= "Xaa denotes V or I at residue #1; F or Y                              at residue #2; F,Y,I or L at residue #3; F,Y,I or                             L at residue #4; R or T at residue #6; and T or N                             at residue #8"                                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:                                      XaaXaaXaaXaaPheXaaXaaXaa                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:24:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ24                                           /note= "Xaa denotes V or I at residue #1; F or Y                              at residue #2; F,Y,I or L at residue #3; F,Y,I or                             L at residue #4; F or Y at residue #5; R or T at                              residue #6; E,D or V at residue #7; and T or N at                             residue #8"                                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:                                      XaaXaaXaaXaaXaaXaaXaaXaa                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:25:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ25                                           /note= "Xaa denotes F or Y at residue #2; and C or                            S at residue #5"                                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:                                      GluXaaIleAsnXaaGlyLys                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:26:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ26                                           /note= "Xaa denotes F or Y at residue #1; and A,V                             or I at residue #7"                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:                                      XaaIleAsnCysGlyLysXaa                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:27:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ27                                           /note= "Xaa denotes V or I at residue #2; A or G                              at residue #3; R or Q at residue #4; and V or I at                            residue #5"                                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:                                      ArgXaaXaaXaaXaaCysLys                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:28:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..9                                                            (D) OTHER INFORMATION: /label=SEQ28                                           /note= "Xaa denotes V or I at residue #2; R or Q                              at residue #4; and V or I at residue #5"                                      (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:                                      ArgXaaXaaXaaXaaCysXaaXaaAsp                                                   15                                                                            (2) INFORMATION FOR SEQ ID NO:29:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..13                                                           (D) OTHER INFORMATION: /label=SEQ29                                           /note= "Xaa denotes V,A or I at residue #3; and                               V,A or I at residue #8"                                                       (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:                                      GlyLysXaaXaaXaaXaaArgXaaXaaXaaXaaCysLys                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO:30:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ30                                           /note= "Xaa denotes R,K or N at residue #1; T,A or                            S at residue #3; T,A or S at residue #4; F,Y or L                             at residue #5; and K or R at residue #7"                                      (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:                                      XaaTrpXaaXaaXaaLeuXaa                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:31:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ31                                           /note= "Xaa denotes F or Y at residue #1; K or R                              at residue #3; A or S at residue #4; and N or I at                            residue #7"                                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:                                      XaaLeuXaaXaaArgLeuXaaCys                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:32:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..6                                                            (D) OTHER INFORMATION: /label=SEQ32                                           /note= "Xaa denotes N or I at residue #1; I or V                              at residue #4; and P or S at residue #5"                                      (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:                                      XaaCysSerXaaXaaGly                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:33:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..9                                                            (D) OTHER INFORMATION: /label=SEQ33                                           /note= "Xaa denotes T,A or S at residue #2; T,A or                            S at residue #3; F,Y or L at residue #4; and                                  A,S,V,I or L at residue #7"                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:                                      TrpXaaXaaXaaLeuLysXaaXaaLeu                                                   15                                                                            (2) INFORMATION FOR SEQ ID NO:34:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..11                                                           (D) OTHER INFORMATION: /label=SEQ34                                           /note= "Xaa denotes T,A or S at residue #2; and                               T,A or S at residue #3"                                                       (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:                                      TrpXaaXaaXaaLeuLysXaaXaaLeuXaaCys                                             1510                                                                          (2) INFORMATION FOR SEQ ID NO:35:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..11                                                           (D) OTHER INFORMATION: /label=SEQ35                                           /note= "Xaa denotes T or S at residue #3"                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:                                      TrpXaaXaaXaaLeuLysXaaXaaLeuXaaCys                                             1510                                                                          (2) INFORMATION FOR SEQ ID NO:36:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ36                                           /note= "Xaa denotes F or Y at residue #1; F or Y                              at residue #2; and N or D at residue #3"                                      (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:                                      XaaXaaXaaGluIleGlnSer                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:37:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ37                                           /note= "Xaa denotes F or Y at residue #1; F or Y                              at residue #3; F or Y at residue #4; F or Y at                                residue #5; and N or D at residue #6"                                         (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:                                      XaaProXaaXaaXaaXaaGlu                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:38:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ38                                           /note= "Xaa denotes V,I or L at residue #4; and F                             or Y at residue #7"                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:                                      GlySerAlaXaaCysXaaXaa                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:39:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ39                                           /note= "Xaa denotes V,I or L at residue #3; and F                             or Y at residue #6"                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:                                      SerAlaXaaCysXaaXaaXaaMet                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:40:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ40                                           /note= "Xaa denotes N or A at residue #3; and P or                            A at residue #6"                                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:                                      AsnSerXaaTrpLeuXaaVal                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:41:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ41                                           /note= "Xaa denotes V,L or I at residue #1; and                               E,D,Y,S or F at residue #3"                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:                                      XaaProXaaProArgProGly                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:42:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..9                                                            (D) OTHER INFORMATION: /label=SEQ42                                           /note= "Xaa denotes V,L or I at residue #1; and R                             or A at residue #5"                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:                                      XaaProXaaProXaaProGlyXaaCys                                                   15                                                                            (2) INFORMATION FOR SEQ ID NO:43:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ43                                           /note= "Xaa denotes E,D,Y,S or F at residue #2;                               and T,Q or S at residue #7"                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:                                      ProXaaProArgProGlyXaaCys                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:44:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..6                                                            (D) OTHER INFORMATION: /label=SEQ44                                           /note= "Xaa denotes H,F or Y at residue #3; and A                             or G at residue #5"                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:                                      AspProXaaCysXaaTrp                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:45:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..6                                                            (D) OTHER INFORMATION: /label=SEQ45                                           /note= "Xaa denotes H,F or Y at residue #2; and A                             or G at residue #4"                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:                                      ProXaaCysXaaTrpAsp                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:46:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ46                                           /note= "Xaa denotes A or G at residue #5"                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:                                      AspProXaaCysXaaTrpAsp                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:47:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:                                      CysXaaXaaXaaXaaAspProXaaCysXaaTrpAsp                                          1510                                                                          (2) INFORMATION FOR SEQ ID NO:48:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:                                      CysXaaXaaXaaAspProXaaCysXaaTrpAsp                                             1510                                                                          (2) INFORMATION FOR SEQ ID NO:49:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:                                      CysXaaXaaAspProXaaCysXaaTrpAsp                                                1510                                                                          (2) INFORMATION FOR SEQ ID NO:50:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:50:                                      CysXaaXaaCysXaaXaaXaaXaaAspXaaXaaCysXaaTrpAsp                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO:51:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:                                      CysXaaXaaCysXaaXaaXaaAspXaaXaaCysXaaTrpAsp                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:52:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52:                                      CysXaaXaaCysXaaXaaAspXaaXaaCysXaaTrpAsp                                       1510                                                                          (2) INFORMATION FOR SEQ ID NO:53:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 2601 base pairs                                                   (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: cDNA                                                      (ix) FEATURE:                                                                 (A) NAME/KEY: CDS                                                             (B) LOCATION: 16..2331                                                        (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53:                                      GGAATTCCCTGCAGCATGGGCTGGTTAACTAGGATTGTCTGTCTTTTCTGG51                         MetGlyTrpLeuThrArgIleValCysLeuPheTrp                                          1510                                                                          GGAGTATTACTTACAGCAAGAGCAAACTATCAGAATGGGAAGAACAAT99                            GlyValLeuLeuThrAlaArgAlaAsnTyrGlnAsnGlyLysAsnAsn                              152025                                                                        GTGCCAAGGCTGAAATTATCCTACAAAGAAATGTTGGAATCCAACAAT147                           ValProArgLeuLysLeuSerTyrLysGluMetLeuGluSerAsnAsn                              303540                                                                        GTGATCACTTTCAATGGCTTGGCCAACAGCTCCAGTTATCATACCTTC195                           ValIleThrPheAsnGlyLeuAlaAsnSerSerSerTyrHisThrPhe                              45505560                                                                      CTTTTGGATGAGGAACGGAGTAGGCTGTATGTTGGAGCAAAGGATCAC243                           LeuLeuAspGluGluArgSerArgLeuTyrValGlyAlaLysAspHis                              657075                                                                        ATATTTTCATTCGACCTGGTTAATATCAAGGATTTTCAAAAGATTGTG291                           IlePheSerPheAspLeuValAsnIleLysAspPheGlnLysIleVal                              808590                                                                        TGGCCAGTATCTTACACCAGAAGAGATGAATGCAAGTGGGCTGGAAAA339                           TrpProValSerTyrThrArgArgAspGluCysLysTrpAlaGlyLys                              95100105                                                                      GACATCCTGAAAGAATGTGCTAATTTCATCAAGGTACTTAAGGCATAT387                           AspIleLeuLysGluCysAlaAsnPheIleLysValLeuLysAlaTyr                              110115120                                                                     AATCAGACTCACTTGTACGCCTGTGGAACGGGGGCTTTTCATCCAATT435                           AsnGlnThrHisLeuTyrAlaCysGlyThrGlyAlaPheHisProIle                              125130135140                                                                  TGCACCTACATTGAAATTGGACATCATCCTGAGGACAATATTTTTAAG483                           CysThrTyrIleGluIleGlyHisHisProGluAspAsnIlePheLys                              145150155                                                                     CTGGAGAACTCACATTTTGAAAACGGCCGTGGGAAGAGTCCATATGAC531                           LeuGluAsnSerHisPheGluAsnGlyArgGlyLysSerProTyrAsp                              160165170                                                                     CCTAAGCTGCTGACAGCATCCCTTTTAATAGATGGAGAATTATACTCT579                           ProLysLeuLeuThrAlaSerLeuLeuIleAspGlyGluLeuTyrSer                              175180185                                                                     GGAACTGCAGCTGATTTTATGGGGCGAGACTTTGCTATCTTCCGAACT627                           GlyThrAlaAlaAspPheMetGlyArgAspPheAlaIlePheArgThr                              190195200                                                                     CTTGGGCACCACCACCCAATCAGGACAGAGCAGCATGATTCCAGGTGG675                           LeuGlyHisHisHisProIleArgThrGluGlnHisAspSerArgTrp                              205210215220                                                                  CTCAATGATCCAAAGTTCATTAGTGCCCACCTCATCTCAGAGAGTGAC723                           LeuAsnAspProLysPheIleSerAlaHisLeuIleSerGluSerAsp                              225230235                                                                     AATCCTGAAGATGACAAAGTATACTTTTTCTTCCGTGAAAATGCAATA771                           AsnProGluAspAspLysValTyrPhePhePheArgGluAsnAlaIle                              240245250                                                                     GATGGAGAACACTCTGGAAAAGCTACTCACGCTAGAATAGGTCAGATA819                           AspGlyGluHisSerGlyLysAlaThrHisAlaArgIleGlyGlnIle                              255260265                                                                     TGCAAGAATGACTTTGGAGGGCACAGAAGTCTGGTGAATAAATGGACA867                           CysLysAsnAspPheGlyGlyHisArgSerLeuValAsnLysTrpThr                              270275280                                                                     ACATTCCTCAAAGCTCGTCTGATTTGCTCAGTGCCAGGTCCAAATGGC915                           ThrPheLeuLysAlaArgLeuIleCysSerValProGlyProAsnGly                              285290295300                                                                  ATTGACACTCATTTTGATGAACTGCAGGATGTATTCCTAATGAACTTT963                           IleAspThrHisPheAspGluLeuGlnAspValPheLeuMetAsnPhe                              305310315                                                                     AAAGATCCTAAAAATCCAGTTGTATATGGAGTGTTTACGACTTCCAGT1011                          LysAspProLysAsnProValValTyrGlyValPheThrThrSerSer                              320325330                                                                     AACATTTTCAAGGGATCAGCCGTGTGTATGTATAGCATGAGTGATGTG1059                          AsnIlePheLysGlySerAlaValCysMetTyrSerMetSerAspVal                              335340345                                                                     AGAAGGGTGTTCCTTGGTCCATATGCCCACAGGGATGGACCCAACTAT1107                          ArgArgValPheLeuGlyProTyrAlaHisArgAspGlyProAsnTyr                              350355360                                                                     CAATGGGTGCCTTATCAAGGAAGAGTCCCCTATCCACGGCCAGGAACT1155                          GlnTrpValProTyrGlnGlyArgValProTyrProArgProGlyThr                              365370375380                                                                  TGTCCCAGCAAAACATTTGGTGGTTTTGACTCTACAAAGGACCTTCCT1203                          CysProSerLysThrPheGlyGlyPheAspSerThrLysAspLeuPro                              385390395                                                                     GATGATGTTATAACCTTTGCAAGAAGTCATCCAGCCATGTACAATCCA1251                          AspAspValIleThrPheAlaArgSerHisProAlaMetTyrAsnPro                              400405410                                                                     GTGTTTCCTATGAACAATCGCCCAATAGTGATCAAAACGGATGTAAAT1299                          ValPheProMetAsnAsnArgProIleValIleLysThrAspValAsn                              415420425                                                                     TATCAATTTACACAAATTGTCGTAGACCGAGTGGATGCAGAAGATGGA1347                          TyrGlnPheThrGlnIleValValAspArgValAspAlaGluAspGly                              430435440                                                                     CAGTATGATGTTATGTTTATCGGAACAGATGTTGGGACCGTTCTTAAA1395                          GlnTyrAspValMetPheIleGlyThrAspValGlyThrValLeuLys                              445450455460                                                                  GTAGTTTCAATTCCTAAGGAGACTTGGTATGATTTAGAAGAGGTTCTG1443                          ValValSerIleProLysGluThrTrpTyrAspLeuGluGluValLeu                              465470475                                                                     CTGGAAGAAATGACAGTTTTTCGGGAACCGACTGCTATTTCAGCAATG1491                          LeuGluGluMetThrValPheArgGluProThrAlaIleSerAlaMet                              480485490                                                                     GAGCTTTCCACTAAGCAGCAACAACTATATATTGGTTCAACGGCTGGG1539                          GluLeuSerThrLysGlnGlnGlnLeuTyrIleGlySerThrAlaGly                              495500505                                                                     GTTGCCCAGCTCCCTTTACACCGGTGTGATATTTACGGGAAAGCGTGT1587                          ValAlaGlnLeuProLeuHisArgCysAspIleTyrGlyLysAlaCys                              510515520                                                                     GCTGAGTGTTGCCTCGCCCGAGACCCTTACTGTGCTTGGGATGGTTCT1635                          AlaGluCysCysLeuAlaArgAspProTyrCysAlaTrpAspGlySer                              525530535540                                                                  GCATGTTCTCGCTATTTTCCCACTGCAAAGAGACGCACAAGACGACAA1683                          AlaCysSerArgTyrPheProThrAlaLysArgArgThrArgArgGln                              545550555                                                                     GATATAAGAAATGGAGACCCACTGACTCACTGTTCAGACTTACACCAT1731                          AspIleArgAsnGlyAspProLeuThrHisCysSerAspLeuHisHis                              560565570                                                                     GATAATCACCATGGCCACAGCCCTGAAGAGAGAATCATCTATGGTGTA1779                          AspAsnHisHisGlyHisSerProGluGluArgIleIleTyrGlyVal                              575580585                                                                     GAGAATAGTAGCACATTTTTGGAATGCAGTCCGAAGTCGCAGAGAGCG1827                          GluAsnSerSerThrPheLeuGluCysSerProLysSerGlnArgAla                              590595600                                                                     CTGGTCTATTGGCAATTCCAGAGGCGAAATGAAGAGCGAAAAGAAGAG1875                          LeuValTyrTrpGlnPheGlnArgArgAsnGluGluArgLysGluGlu                              605610615620                                                                  ATCAGAGTGGATGATCATATCATCAGGACAGATCAAGGCCTTCTGCTA1923                          IleArgValAspAspHisIleIleArgThrAspGlnGlyLeuLeuLeu                              625630635                                                                     CGTAGTCTACAACAGAAGGATTCAGGCAATTACCTCTGCCATGCGGTG1971                          ArgSerLeuGlnGlnLysAspSerGlyAsnTyrLeuCysHisAlaVal                              640645650                                                                     GAACATGGGTTCATACAAACTCTTCTTAAGGTAACCCTGGAAGTCATT2019                          GluHisGlyPheIleGlnThrLeuLeuLysValThrLeuGluValIle                              655660665                                                                     GACACAGAGCATTTGGAAGAACTTCTTCATAAAGATGATGATGGAGAT2067                          AspThrGluHisLeuGluGluLeuLeuHisLysAspAspAspGlyAsp                              670675680                                                                     GGCTCTAAGACCAAAGAAATGTCCAATAGCATGACACCTAGCCAGAAG2115                          GlySerLysThrLysGluMetSerAsnSerMetThrProSerGlnLys                              685690695700                                                                  GTCTGGTACAGAGACTTCATGCAGCTCATCAACCACCCCAATCTCAAC2163                          ValTrpTyrArgAspPheMetGlnLeuIleAsnHisProAsnLeuAsn                              705710715                                                                     ACGATGGATGAGTTCTGTGAACAAGTTTGGAAAAGGGACCGAAAACAA2211                          ThrMetAspGluPheCysGluGlnValTrpLysArgAspArgLysGln                              720725730                                                                     CGTCGGCAAAGGCCAGGACATACCCCAGGGAACAGTAACAAATGGAAG2259                          ArgArgGlnArgProGlyHisThrProGlyAsnSerAsnLysTrpLys                              735740745                                                                     CACTTACAAGAAAATAAGAAAGGTAGAAACAGGAGGACCCACGAATTT2307                          HisLeuGlnGluAsnLysLysGlyArgAsnArgArgThrHisGluPhe                              750755760                                                                     GAGAGGGCACCCAGGAGTGTCTGAGCTGCATTACCTCTAGAAACCTCAAAC2358                       GluArgAlaProArgSerVal                                                         765770                                                                        AAGTAGAAACTTGCCTAGACAATAACTGGAAAAACAAATGCAATATACATGAACTTTTTT2418              CATGGCATTATGTGGATGTTTACAATGGTGGGAAATTCAGCTGAGTTCCACCAATTATAA2478              ATTAAATCCATGAGTAACTTTCCTAATAGGCTTTTTTTTCCTAATACCACCGGGTTAAAA2538              GTAAGAGACAGCTGAACCCTCGTGGAGCCATTCATACAGGTCCCTATTTAAGGAACGGAA2598              TTC2601                                                                       (2) INFORMATION FOR SEQ ID NO:54:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 771 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: protein                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54:                                      MetGlyTrpLeuThrArgIleValCysLeuPheTrpGlyValLeuLeu                              151015                                                                        ThrAlaArgAlaAsnTyrGlnAsnGlyLysAsnAsnValProArgLeu                              202530                                                                        LysLeuSerTyrLysGluMetLeuGluSerAsnAsnValIleThrPhe                              354045                                                                        AsnGlyLeuAlaAsnSerSerSerTyrHisThrPheLeuLeuAspGlu                              505560                                                                        GluArgSerArgLeuTyrValGlyAlaLysAspHisIlePheSerPhe                              65707580                                                                      AspLeuValAsnIleLysAspPheGlnLysIleValTrpProValSer                              859095                                                                        TyrThrArgArgAspGluCysLysTrpAlaGlyLysAspIleLeuLys                              100105110                                                                     GluCysAlaAsnPheIleLysValLeuLysAlaTyrAsnGlnThrHis                              115120125                                                                     LeuTyrAlaCysGlyThrGlyAlaPheHisProIleCysThrTyrIle                              130135140                                                                     GluIleGlyHisHisProGluAspAsnIlePheLysLeuGluAsnSer                              145150155160                                                                  HisPheGluAsnGlyArgGlyLysSerProTyrAspProLysLeuLeu                              165170175                                                                     ThrAlaSerLeuLeuIleAspGlyGluLeuTyrSerGlyThrAlaAla                              180185190                                                                     AspPheMetGlyArgAspPheAlaIlePheArgThrLeuGlyHisHis                              195200205                                                                     HisProIleArgThrGluGlnHisAspSerArgTrpLeuAsnAspPro                              210215220                                                                     LysPheIleSerAlaHisLeuIleSerGluSerAspAsnProGluAsp                              225230235240                                                                  AspLysValTyrPhePhePheArgGluAsnAlaIleAspGlyGluHis                              245250255                                                                     SerGlyLysAlaThrHisAlaArgIleGlyGlnIleCysLysAsnAsp                              260265270                                                                     PheGlyGlyHisArgSerLeuValAsnLysTrpThrThrPheLeuLys                              275280285                                                                     AlaArgLeuIleCysSerValProGlyProAsnGlyIleAspThrHis                              290295300                                                                     PheAspGluLeuGlnAspValPheLeuMetAsnPheLysAspProLys                              305310315320                                                                  AsnProValValTyrGlyValPheThrThrSerSerAsnIlePheLys                              325330335                                                                     GlySerAlaValCysMetTyrSerMetSerAspValArgArgValPhe                              340345350                                                                     LeuGlyProTyrAlaHisArgAspGlyProAsnTyrGlnTrpValPro                              355360365                                                                     TyrGlnGlyArgValProTyrProArgProGlyThrCysProSerLys                              370375380                                                                     ThrPheGlyGlyPheAspSerThrLysAspLeuProAspAspValIle                              385390395400                                                                  ThrPheAlaArgSerHisProAlaMetTyrAsnProValPheProMet                              405410415                                                                     AsnAsnArgProIleValIleLysThrAspValAsnTyrGlnPheThr                              420425430                                                                     GlnIleValValAspArgValAspAlaGluAspGlyGlnTyrAspVal                              435440445                                                                     MetPheIleGlyThrAspValGlyThrValLeuLysValValSerIle                              450455460                                                                     ProLysGluThrTrpTyrAspLeuGluGluValLeuLeuGluGluMet                              465470475480                                                                  ThrValPheArgGluProThrAlaIleSerAlaMetGluLeuSerThr                              485490495                                                                     LysGlnGlnGlnLeuTyrIleGlySerThrAlaGlyValAlaGlnLeu                              500505510                                                                     ProLeuHisArgCysAspIleTyrGlyLysAlaCysAlaGluCysCys                              515520525                                                                     LeuAlaArgAspProTyrCysAlaTrpAspGlySerAlaCysSerArg                              530535540                                                                     TyrPheProThrAlaLysArgArgThrArgArgGlnAspIleArgAsn                              545550555560                                                                  GlyAspProLeuThrHisCysSerAspLeuHisHisAspAsnHisHis                              565570575                                                                     GlyHisSerProGluGluArgIleIleTyrGlyValGluAsnSerSer                              580585590                                                                     ThrPheLeuGluCysSerProLysSerGlnArgAlaLeuValTyrTrp                              595600605                                                                     GlnPheGlnArgArgAsnGluGluArgLysGluGluIleArgValAsp                              610615620                                                                     AspHisIleIleArgThrAspGlnGlyLeuLeuLeuArgSerLeuGln                              625630635640                                                                  GlnLysAspSerGlyAsnTyrLeuCysHisAlaValGluHisGlyPhe                              645650655                                                                     IleGlnThrLeuLeuLysValThrLeuGluValIleAspThrGluHis                              660665670                                                                     LeuGluGluLeuLeuHisLysAspAspAspGlyAspGlySerLysThr                              675680685                                                                     LysGluMetSerAsnSerMetThrProSerGlnLysValTrpTyrArg                              690695700                                                                     AspPheMetGlnLeuIleAsnHisProAsnLeuAsnThrMetAspGlu                              705710715720                                                                  PheCysGluGlnValTrpLysArgAspArgLysGlnArgArgGlnArg                              725730735                                                                     ProGlyHisThrProGlyAsnSerAsnLysTrpLysHisLeuGlnGlu                              740745750                                                                     AsnLysLysGlyArgAsnArgArgThrHisGluPheGluArgAlaPro                              755760765                                                                     ArgSerVal                                                                     770                                                                           (2) INFORMATION FOR SEQ ID NO:55:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 1332 base pairs                                                   (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: cDNA                                                      (ix) FEATURE:                                                                 (A) NAME/KEY: CDS                                                             (B) LOCATION: 7..1329                                                         (xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:                                      GGAATAATGATGGTATTATTACATGCTGTATACTCTATAGTCTTTGTA48                            MetMetValLeuLeuHisAlaValTyrSerIleValPheVal                                    1510                                                                          GATGTTATAATCATAAAAGTACAGAGGTATATCAACGATATTCTAACT96                            AspValIleIleIleLysValGlnArgTyrIleAsnAspIleLeuThr                              15202530                                                                      CTTGACATTTTTTATTTATTTAAAATGATACCTTTGTTATTTATTTTA144                           LeuAspIlePheTyrLeuPheLysMetIleProLeuLeuPheIleLeu                              354045                                                                        TTCTATTTTGCTAACGGTATCGAATGGCATAAGTTTGAAACGAGTGAA192                           PheTyrPheAlaAsnGlyIleGluTrpHisLysPheGluThrSerGlu                              505560                                                                        GAAATAATTTCTACTTACTTATTAGACGACGTATTATACACGGGTGTT240                           GluIleIleSerThrTyrLeuLeuAspAspValLeuTyrThrGlyVal                              657075                                                                        AATGGGGCGGTATACACATTTTCAAATAATAAACTAAACAAAACTGGT288                           AsnGlyAlaValTyrThrPheSerAsnAsnLysLeuAsnLysThrGly                              808590                                                                        TTAACTAATAATAATTATATAACAACATCTATAAAAGTAGAGGATGCG336                           LeuThrAsnAsnAsnTyrIleThrThrSerIleLysValGluAspAla                              95100105110                                                                   GATAAGGATACATTAGTATGCGGAACCAATAACGGAAATCCCAAATGT384                           AspLysAspThrLeuValCysGlyThrAsnAsnGlyAsnProLysCys                              115120125                                                                     TGGAAAATAGACGGTTCAGACGACCCAAAACATAGAGGTAGAGGATAC432                           TrpLysIleAspGlySerAspAspProLysHisArgGlyArgGlyTyr                              130135140                                                                     GCTCCTTATCAAAATAGCAAAGTAACGATAATCAGTCACAACGGATGT480                           AlaProTyrGlnAsnSerLysValThrIleIleSerHisAsnGlyCys                              145150155                                                                     GTACTATCTGACATAAACATATCAAAAGAAGGAATTAAACGATGGAGA528                           ValLeuSerAspIleAsnIleSerLysGluGlyIleLysArgTrpArg                              160165170                                                                     AGATTTGACGGACCATGTGGTTATGATTTATACACGGCGGATAACGTA576                           ArgPheAspGlyProCysGlyTyrAspLeuTyrThrAlaAspAsnVal                              175180185190                                                                  ATTCCAAAAGATGGTTTACGAGGAGCATTCGTCGATAAAGATGGTACT624                           IleProLysAspGlyLeuArgGlyAlaPheValAspLysAspGlyThr                              195200205                                                                     TATGACAAAGTTTACATTCTTTTCACTGATACTATCGGCTCAAAGAGA672                           TyrAspLysValTyrIleLeuPheThrAspThrIleGlySerLysArg                              210215220                                                                     ATTGTCAAAATTCCGTATATAGCACAAATGTGCCTAAACGACGAAGGT720                           IleValLysIleProTyrIleAlaGlnMetCysLeuAsnAspGluGly                              225230235                                                                     GGTCCATCATCATTGTCTAGTCATAGATGGTCGACGTTTCTCAAAGTC768                           GlyProSerSerLeuSerSerHisArgTrpSerThrPheLeuLysVal                              240245250                                                                     GAATTAGAATGTGATATCGACGGAAGAAGTTATAGACAAATTATTCAT816                           GluLeuGluCysAspIleAspGlyArgSerTyrArgGlnIleIleHis                              255260265270                                                                  TCTAGAACTATAAAAACAGATAATGATACGATACTATATGTATTCTTC864                           SerArgThrIleLysThrAspAsnAspThrIleLeuTyrValPhePhe                              275280285                                                                     GATAGTCCTTATTCCAAGTCCGCATTATGTACCTATTCTATGAATACC912                           AspSerProTyrSerLysSerAlaLeuCysThrTyrSerMetAsnThr                              290295300                                                                     ATTAAACAATCTTTTTCTACGTCAAAATTGGAAGGATATACAAAGCAA960                           IleLysGlnSerPheSerThrSerLysLeuGluGlyTyrThrLysGln                              305310315                                                                     TTGCCGTCGCCAGCCTCTGGTATATGTCTACCAGCTGGAAAAGTTGTT1008                          LeuProSerProAlaSerGlyIleCysLeuProAlaGlyLysValVal                              320325330                                                                     CCACATACCACGTTTGAAGTCATAGAAAAATATAATGTACTAGATGAT1056                          ProHisThrThrPheGluValIleGluLysTyrAsnValLeuAspAsp                              335340345350                                                                  ATTATAAAGCCTTTATCTAACCAACCTATCTTCGAAGGACCGTCTGGT1104                          IleIleLysProLeuSerAsnGlnProIlePheGluGlyProSerGly                              355360365                                                                     GTTAAATGGTTCGATATAAAGGAGAAGGAAAATGAACATCGGGAATAT1152                          ValLysTrpPheAspIleLysGluLysGluAsnGluHisArgGluTyr                              370375380                                                                     AGAATATACTTCATAAAAGAAAATTCTATATATTCGTTCGATACAAAA1200                          ArgIleTyrPheIleLysGluAsnSerIleTyrSerPheAspThrLys                              385390395                                                                     TCTAAACAAACTCGTAGCTCGCAAGTCGATGCGCGACTATTTTCAGTA1248                          SerLysGlnThrArgSerSerGlnValAspAlaArgLeuPheSerVal                              400405410                                                                     ATGGTAACTTCGAAACCGTTATTTATAGCAGATATAGGGATAGGAGTA1296                          MetValThrSerLysProLeuPheIleAlaAspIleGlyIleGlyVal                              415420425430                                                                  GGAATGCCACAAATGAAAAAAATACTTAAAATGTAA1332                                      GlyMetProGlnMetLysLysIleLeuLysMet                                             435440                                                                        (2) INFORMATION FOR SEQ ID NO:56:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 441 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: protein                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56:                                      MetMetValLeuLeuHisAlaValTyrSerIleValPheValAspVal                              151015                                                                        IleIleIleLysValGlnArgTyrIleAsnAspIleLeuThrLeuAsp                              202530                                                                        IlePheTyrLeuPheLysMetIleProLeuLeuPheIleLeuPheTyr                              354045                                                                        PheAlaAsnGlyIleGluTrpHisLysPheGluThrSerGluGluIle                              505560                                                                        IleSerThrTyrLeuLeuAspAspValLeuTyrThrGlyValAsnGly                              65707580                                                                      AlaValTyrThrPheSerAsnAsnLysLeuAsnLysThrGlyLeuThr                              859095                                                                        AsnAsnAsnTyrIleThrThrSerIleLysValGluAspAlaAspLys                              100105110                                                                     AspThrLeuValCysGlyThrAsnAsnGlyAsnProLysCysTrpLys                              115120125                                                                     IleAspGlySerAspAspProLysHisArgGlyArgGlyTyrAlaPro                              130135140                                                                     TyrGlnAsnSerLysValThrIleIleSerHisAsnGlyCysValLeu                              145150155160                                                                  SerAspIleAsnIleSerLysGluGlyIleLysArgTrpArgArgPhe                              165170175                                                                     AspGlyProCysGlyTyrAspLeuTyrThrAlaAspAsnValIlePro                              180185190                                                                     LysAspGlyLeuArgGlyAlaPheValAspLysAspGlyThrTyrAsp                              195200205                                                                     LysValTyrIleLeuPheThrAspThrIleGlySerLysArgIleVal                              210215220                                                                     LysIleProTyrIleAlaGlnMetCysLeuAsnAspGluGlyGlyPro                              225230235240                                                                  SerSerLeuSerSerHisArgTrpSerThrPheLeuLysValGluLeu                              245250255                                                                     GluCysAspIleAspGlyArgSerTyrArgGlnIleIleHisSerArg                              260265270                                                                     ThrIleLysThrAspAsnAspThrIleLeuTyrValPhePheAspSer                              275280285                                                                     ProTyrSerLysSerAlaLeuCysThrTyrSerMetAsnThrIleLys                              290295300                                                                     GlnSerPheSerThrSerLysLeuGluGlyTyrThrLysGlnLeuPro                              305310315320                                                                  SerProAlaSerGlyIleCysLeuProAlaGlyLysValValProHis                              325330335                                                                     ThrThrPheGluValIleGluLysTyrAsnValLeuAspAspIleIle                              340345350                                                                     LysProLeuSerAsnGlnProIlePheGluGlyProSerGlyValLys                              355360365                                                                     TrpPheAspIleLysGluLysGluAsnGluHisArgGluTyrArgIle                              370375380                                                                     TyrPheIleLysGluAsnSerIleTyrSerPheAspThrLysSerLys                              385390395400                                                                  GlnThrArgSerSerGlnValAspAlaArgLeuPheSerValMetVal                              405410415                                                                     ThrSerLysProLeuPheIleAlaAspIleGlyIleGlyValGlyMet                              420425430                                                                     ProGlnMetLysLysIleLeuLysMet                                                   435440                                                                        (2) INFORMATION FOR SEQ ID NO:57:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 2854 base pairs                                                   (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: cDNA                                                      (ix) FEATURE:                                                                 (A) NAME/KEY: CDS                                                             (B) LOCATION: 451..2640                                                       (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57:                                      ATTCCACCTCCCGCTGACCGCCTACGCCGCGACGATCTTTCCTCTCGCCAGGCGAAAACT60                ACGACGTGTCAACAACATTTTTGTTTTTTCTGCTTCCGTGTTTTCATGTTCCGTGAAACC120               GCTTCTCGCATTACCACTCTTCCGTTTCCCAGTGTTTGTTTTCTCCGTTTCTTTCATCGT180               GGATGTTTTGTTTTGGTGTAGCGAGTGACGAGCTTATGTCATTAAACGTACATCCAATCT240               GTCGGTATATTGGTGTGTGATATTTTACTATTATATATTTAGCCATCACTTGAAAGCCGT300               GAAAAATTTTTGAAAGTGGAGAGGAAAAAGAAAAGGCGCAGAAGGCTTTTTAAGCTTCAT360               GGATATGTGCTCTACGCTTCAACTACTGTCGCAGAATCATCTTCCGGGAAAGGAAATTTC420               GCCTGAAATGGTGCCGCGGCCGCACTGAACATGCGGGCGGCGCTGGTGGCCGTC474                     MetArgAlaAlaLeuValAlaVal                                                      15                                                                            GCGGCGCTGCTTTGGGTGGCGCTGCACGCCGCCGCATGGGTCAACGAC522                           AlaAlaLeuLeuTrpValAlaLeuHisAlaAlaAlaTrpValAsnAsp                              101520                                                                        GTCAGCCCCAAGATGTACGTCCAGTTCGGTGAGGAACGGGTGCAACGC570                           ValSerProLysMetTyrValGlnPheGlyGluGluArgValGlnArg                              25303540                                                                      TTCCTGGGCAATGAATCGCACAAAGACCACTTCAAGCTGCTGGAGAAG618                           PheLeuGlyAsnGluSerHisLysAspHisPheLysLeuLeuGluLys                              455055                                                                        GACCACAACTCGCTCCTCGTAGGAGCTAGGAACATCGTCTACAATATC666                           AspHisAsnSerLeuLeuValGlyAlaArgAsnIleValTyrAsnIle                              606570                                                                        AGCCTTCGAGACCTCACAGAATTCACCGAGCAGAGGATCGAGTGGCAC714                           SerLeuArgAspLeuThrGluPheThrGluGlnArgIleGluTrpHis                              758085                                                                        TCGTCAGGTGCCCATCGCGAGCTCTGCTACCTCAAGGGGAAGTCAGAG762                           SerSerGlyAlaHisArgGluLeuCysTyrLeuLysGlyLysSerGlu                              9095100                                                                       GACGACTGCCAGAACTACATCCGAGTCCTGGCGAAAATTGACGATGAC810                           AspAspCysGlnAsnTyrIleArgValLeuAlaLysIleAspAspAsp                              105110115120                                                                  CGCGTACTCATCTGCGGTACGAACGCCTATAAGCCACTATGTCGGCAC858                           ArgValLeuIleCysGlyThrAsnAlaTyrLysProLeuCysArgHis                              125130135                                                                     TACGCCCTCAAGGATGGAGATTATGTTGTAGAGAAAGAATATGAGGGA906                           TyrAlaLeuLysAspGlyAspTyrValValGluLysGluTyrGluGly                              140145150                                                                     AGAGGATTGTGCCCATTTGACCCTGACCACAACAGCACTGCAATATAC954                           ArgGlyLeuCysProPheAspProAspHisAsnSerThrAlaIleTyr                              155160165                                                                     AGTGAGGGACAATTGTACTCAGCAACAGTGGCAGACTTCTCTGGAACT1002                          SerGluGlyGlnLeuTyrSerAlaThrValAlaAspPheSerGlyThr                              170175180                                                                     GACCCTCTCATATACCGCGGCCCTCTAAGAACAGAGAGATCTGACCTC1050                          AspProLeuIleTyrArgGlyProLeuArgThrGluArgSerAspLeu                              185190195200                                                                  AAACAATTAAATGCTCCTAACTTTGTCAACACAATGGAGTACAATGAT1098                          LysGlnLeuAsnAlaProAsnPheValAsnThrMetGluTyrAsnAsp                              205210215                                                                     TTTATATTCTTCTTCTTCCGAGAGACTGCTGTTGAGTACATCAACTGC1146                          PheIlePhePhePhePheArgGluThrAlaValGluTyrIleAsnCys                              220225230                                                                     GGAAAGGCTATCTATTCAAGAGTTGCCAGAGTCTGTAAACATGACAAG1194                          GlyLysAlaIleTyrSerArgValAlaArgValCysLysHisAspLys                              235240245                                                                     GGCGGCCCTCATCAGGGTGGTGACAGATGGACTTCTTTTTTGAAATCA1242                          GlyGlyProHisGlnGlyGlyAspArgTrpThrSerPheLeuLysSer                              250255260                                                                     CGTCTGAACTGTTCCGTCCCTGGAGATTATCCATTTTACTTCAATGAA1290                          ArgLeuAsnCysSerValProGlyAspTyrProPheTyrPheAsnGlu                              265270275280                                                                  ATTCAGTCAACAAGTGACATCATTGAAGGAAATTATGGTGGTCAAGTG1338                          IleGlnSerThrSerAspIleIleGluGlyAsnTyrGlyGlyGlnVal                              285290295                                                                     GAGAAACTCATCTACGGTGTCTTCACGACACCAGTGAACTCTATTGGT1386                          GluLysLeuIleTyrGlyValPheThrThrProValAsnSerIleGly                              300305310                                                                     GGCTCTGCTGTTTGTGCCTTCAGTATGAAGTCAATACTTGAGTCATTT1434                          GlySerAlaValCysAlaPheSerMetLysSerIleLeuGluSerPhe                              315320325                                                                     GATGGTCCATTTAAAGAGCAGGAAACGATGAACTCAAACTGGTTGGCA1482                          AspGlyProPheLysGluGlnGluThrMetAsnSerAsnTrpLeuAla                              330335340                                                                     GTGCCAAGCCTTAAAGTGCCAGAACCAAGGCCTGGACAATGTGTGAAT1530                          ValProSerLeuLysValProGluProArgProGlyGlnCysValAsn                              345350355360                                                                  GACAGTCGTACACTTCCTGATGTGTCTGTCAATTTTGTAAAGTCACAT1578                          AspSerArgThrLeuProAspValSerValAsnPheValLysSerHis                              365370375                                                                     ACACTGATGGATGAGGCCGTGCCAGCATTTTTTACTCGGCCAATTCTC1626                          ThrLeuMetAspGluAlaValProAlaPhePheThrArgProIleLeu                              380385390                                                                     ATTCGGATCAGCTTACAGTACAGATTTACAAAAATAGCTGTTGATCAA1674                          IleArgIleSerLeuGlnTyrArgPheThrLysIleAlaValAspGln                              395400405                                                                     CAAGTCCGAACACCAGATGGGAAAGCGTATGATGTCCTGTTTATAGGA1722                          GlnValArgThrProAspGlyLysAlaTyrAspValLeuPheIleGly                              410415420                                                                     ACTGATGATGGCAAAGTGATAAAAGCTTTGAACTCTGCCTCCTTTGAT1770                          ThrAspAspGlyLysValIleLysAlaLeuAsnSerAlaSerPheAsp                              425430435440                                                                  TCATCTGATACTGTAGATAGTGTTGTAATAGAAGAACTGCAAGTGTTG1818                          SerSerAspThrValAspSerValValIleGluGluLeuGlnValLeu                              445450455                                                                     CCACCTGGAGTACCTGTTAAGAACCTGTATGTGGTGCGAATGGATGGG1866                          ProProGlyValProValLysAsnLeuTyrValValArgMetAspGly                              460465470                                                                     GATGATAGCAAGCTGGTGGTTGTGTCTGATGATGAGATTCTGGCAATT1914                          AspAspSerLysLeuValValValSerAspAspGluIleLeuAlaIle                              475480485                                                                     AAGCTTCATCGTTGTGGCTCAGATAAAATAACAAATTGTCGAGAATGT1962                          LysLeuHisArgCysGlySerAspLysIleThrAsnCysArgGluCys                              490495500                                                                     GTGTCCTTGCAAGATCCTTACTGTGCATGGGACAATGTAGAATTAAAA2010                          ValSerLeuGlnAspProTyrCysAlaTrpAspAsnValGluLeuLys                              505510515520                                                                  TGTACAGCTGTAGGTTCACCAGACTGGAGTGCTGGAAAAAGACGCTTT2058                          CysThrAlaValGlySerProAspTrpSerAlaGlyLysArgArgPhe                              525530535                                                                     ATTCAGAACATTTCACTCGGTGAACATAAAGCTTGTGGTGGACGTCCA2106                          IleGlnAsnIleSerLeuGlyGluHisLysAlaCysGlyGlyArgPro                              540545550                                                                     CAAACAGAAATCGTTGCTTCTCCTGTACCAACTCAGCCGACGACAAAA2154                          GlnThrGluIleValAlaSerProValProThrGlnProThrThrLys                              555560565                                                                     TCTAGTGGCGATCCCGTTCATTCAATCCACCAGGCTGAATTTGAACCT2202                          SerSerGlyAspProValHisSerIleHisGlnAlaGluPheGluPro                              570575580                                                                     GAAATTGACAACGAGATTGTTATTGGAGTAGATGACAGCAACGTCATT2250                          GluIleAspAsnGluIleValIleGlyValAspAspSerAsnValIle                              585590595600                                                                  CCTAATACCCTGGCTGAAATAAATCATGCAGGTTCAAAGCTGCCTTCC2298                          ProAsnThrLeuAlaGluIleAsnHisAlaGlySerLysLeuProSer                              605610615                                                                     TCCCAGGAAAAGTTGCCTATTTATACAGCGGAGACTCTGACTATTGCT2346                          SerGlnGluLysLeuProIleTyrThrAlaGluThrLeuThrIleAla                              620625630                                                                     ATAGTTACATCATGCCTTGGAGCTCTAGTTGTTGGCTTCATCTCTGGA2394                          IleValThrSerCysLeuGlyAlaLeuValValGlyPheIleSerGly                              635640645                                                                     TTTCTTTTTTCTCGGCGATGCAGGGGAGAGGATTACACAGACATGCCT2442                          PheLeuPheSerArgArgCysArgGlyGluAspTyrThrAspMetPro                              650655660                                                                     TTTCCAGATCAACGCCATCAGCTAAATAGGCTCACTGAGGCTGGTCTG2490                          PheProAspGlnArgHisGlnLeuAsnArgLeuThrGluAlaGlyLeu                              665670675680                                                                  AATGCAGACTCACCCTATCTTCCACCCTGTGCCAATAACAAGGCAGCC2538                          AsnAlaAspSerProTyrLeuProProCysAlaAsnAsnLysAlaAla                              685690695                                                                     ATAAATCTTGTGCTCAATGTCCCACCAAAGAATGCAAATGGAAAAAAT2586                          IleAsnLeuValLeuAsnValProProLysAsnAlaAsnGlyLysAsn                              700705710                                                                     GCCAACTCTTCAGCTGAAAACAAACCAATACAGAAAGTAAAAAAGACA2634                          AlaAsnSerSerAlaGluAsnLysProIleGlnLysValLysLysThr                              715720725                                                                     TACATTTAGCAGAAATCTTTGGTATCTGTTTTGGTGCAGACCCATGCCACTAGAGT2690                  TyrIle                                                                        730                                                                           AACCAAGACTCTATTGAGAAATGTCCTCAAGAAAGTTAAAAAGATGTAGACTTCTGTAAT2750              CGAGAGCACCACTTTCCATAGTAATACAGAACAATGTGAAATAAATACTACAGAAGAAGT2810              CTTTGTTACACAAAAAAGTGTATAGTGATCTGTGATCAGTTTCG2854                              (2) INFORMATION FOR SEQ ID NO:58:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 730 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: protein                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:58:                                      MetArgAlaAlaLeuValAlaValAlaAlaLeuLeuTrpValAlaLeu                              151015                                                                        HisAlaAlaAlaTrpValAsnAspValSerProLysMetTyrValGln                              202530                                                                        PheGlyGluGluArgValGlnArgPheLeuGlyAsnGluSerHisLys                              354045                                                                        AspHisPheLysLeuLeuGluLysAspHisAsnSerLeuLeuValGly                              505560                                                                        AlaArgAsnIleValTyrAsnIleSerLeuArgAspLeuThrGluPhe                              65707580                                                                      ThrGluGlnArgIleGluTrpHisSerSerGlyAlaHisArgGluLeu                              859095                                                                        CysTyrLeuLysGlyLysSerGluAspAspCysGlnAsnTyrIleArg                              100105110                                                                     ValLeuAlaLysIleAspAspAspArgValLeuIleCysGlyThrAsn                              115120125                                                                     AlaTyrLysProLeuCysArgHisTyrAlaLeuLysAspGlyAspTyr                              130135140                                                                     ValValGluLysGluTyrGluGlyArgGlyLeuCysProPheAspPro                              145150155160                                                                  AspHisAsnSerThrAlaIleTyrSerGluGlyGlnLeuTyrSerAla                              165170175                                                                     ThrValAlaAspPheSerGlyThrAspProLeuIleTyrArgGlyPro                              180185190                                                                     LeuArgThrGluArgSerAspLeuLysGlnLeuAsnAlaProAsnPhe                              195200205                                                                     ValAsnThrMetGluTyrAsnAspPheIlePhePhePhePheArgGlu                              210215220                                                                     ThrAlaValGluTyrIleAsnCysGlyLysAlaIleTyrSerArgVal                              225230235240                                                                  AlaArgValCysLysHisAspLysGlyGlyProHisGlnGlyGlyAsp                              245250255                                                                     ArgTrpThrSerPheLeuLysSerArgLeuAsnCysSerValProGly                              260265270                                                                     AspTyrProPheTyrPheAsnGluIleGlnSerThrSerAspIleIle                              275280285                                                                     GluGlyAsnTyrGlyGlyGlnValGluLysLeuIleTyrGlyValPhe                              290295300                                                                     ThrThrProValAsnSerIleGlyGlySerAlaValCysAlaPheSer                              305310315320                                                                  MetLysSerIleLeuGluSerPheAspGlyProPheLysGluGlnGlu                              325330335                                                                     ThrMetAsnSerAsnTrpLeuAlaValProSerLeuLysValProGlu                              340345350                                                                     ProArgProGlyGlnCysValAsnAspSerArgThrLeuProAspVal                              355360365                                                                     SerValAsnPheValLysSerHisThrLeuMetAspGluAlaValPro                              370375380                                                                     AlaPhePheThrArgProIleLeuIleArgIleSerLeuGlnTyrArg                              385390395400                                                                  PheThrLysIleAlaValAspGlnGlnValArgThrProAspGlyLys                              405410415                                                                     AlaTyrAspValLeuPheIleGlyThrAspAspGlyLysValIleLys                              420425430                                                                     AlaLeuAsnSerAlaSerPheAspSerSerAspThrValAspSerVal                              435440445                                                                     ValIleGluGluLeuGlnValLeuProProGlyValProValLysAsn                              450455460                                                                     LeuTyrValValArgMetAspGlyAspAspSerLysLeuValValVal                              465470475480                                                                  SerAspAspGluIleLeuAlaIleLysLeuHisArgCysGlySerAsp                              485490495                                                                     LysIleThrAsnCysArgGluCysValSerLeuGlnAspProTyrCys                              500505510                                                                     AlaTrpAspAsnValGluLeuLysCysThrAlaValGlySerProAsp                              515520525                                                                     TrpSerAlaGlyLysArgArgPheIleGlnAsnIleSerLeuGlyGlu                              530535540                                                                     HisLysAlaCysGlyGlyArgProGlnThrGluIleValAlaSerPro                              545550555560                                                                  ValProThrGlnProThrThrLysSerSerGlyAspProValHisSer                              565570575                                                                     IleHisGlnAlaGluPheGluProGluIleAspAsnGluIleValIle                              580585590                                                                     GlyValAspAspSerAsnValIleProAsnThrLeuAlaGluIleAsn                              595600605                                                                     HisAlaGlySerLysLeuProSerSerGlnGluLysLeuProIleTyr                              610615620                                                                     ThrAlaGluThrLeuThrIleAlaIleValThrSerCysLeuGlyAla                              625630635640                                                                  LeuValValGlyPheIleSerGlyPheLeuPheSerArgArgCysArg                              645650655                                                                     GlyGluAspTyrThrAspMetProPheProAspGlnArgHisGlnLeu                              660665670                                                                     AsnArgLeuThrGluAlaGlyLeuAsnAlaAspSerProTyrLeuPro                              675680685                                                                     ProCysAlaAsnAsnLysAlaAlaIleAsnLeuValLeuAsnValPro                              690695700                                                                     ProLysAsnAlaAsnGlyLysAsnAlaAsnSerSerAlaGluAsnLys                              705710715720                                                                  ProIleGlnLysValLysLysThrTyrIle                                                725730                                                                        (2) INFORMATION FOR SEQ ID NO:59:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 3560 base pairs                                                   (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: cDNA                                                      (ix) FEATURE:                                                                 (A) NAME/KEY: CDS                                                             (B) LOCATION: 1..1953                                                         (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59:                                      GAGGATGATTGTCAGAATTACATCCGCATCATGGTGGTGCCATCGCCG48                            GluAspAspCysGlnAsnTyrIleArgIleMetValValProSerPro                              151015                                                                        GGTCGCCTTTTCGTTTGTGGCACCAACTCGTTCCGGCCCATGTGCAAC96                            GlyArgLeuPheValCysGlyThrAsnSerPheArgProMetCysAsn                              202530                                                                        ACGTATATCATTAGTGACAGCAACTACACGCTGGAGGCCACGAAGAAC144                           ThrTyrIleIleSerAspSerAsnTyrThrLeuGluAlaThrLysAsn                              354045                                                                        GGACAGGCGGTGTGCCCCTACGATCCACGTCACAACTCCACCTCTGTG192                           GlyGlnAlaValCysProTyrAspProArgHisAsnSerThrSerVal                              505560                                                                        CTGGCCGACAACGAACTGTATTCCGGTACCGTGGCGGATTTCAGTGGC240                           LeuAlaAspAsnGluLeuTyrSerGlyThrValAlaAspPheSerGly                              65707580                                                                      AGCGATCCGATTATCTACCGGGAGCCCCTGCAGACCGAGCAGTACGAT288                           SerAspProIleIleTyrArgGluProLeuGlnThrGluGlnTyrAsp                              859095                                                                        AGCCTAAGTCTCAACGCACCGAACTTTGTGAGCTCATTTACGCAGGGC336                           SerLeuSerLeuAsnAlaProAsnPheValSerSerPheThrGlnGly                              100105110                                                                     GACTTTGTCTATTTCTTCTTTCGGGAAACCGCCGTTGAGTTTATCAAC384                           AspPheValTyrPhePhePheArgGluThrAlaValGluPheIleAsn                              115120125                                                                     TGTGGCAAGGCGATTTATTCGCGCGTTGCCCGCGTCTGCAAATGGGAC432                           CysGlyLysAlaIleTyrSerArgValAlaArgValCysLysTrpAsp                              130135140                                                                     AAAGGTGGCCCGCATCGATTCCGCAACCGCTGGACATCCTTCCTCAAG480                           LysGlyGlyProHisArgPheArgAsnArgTrpThrSerPheLeuLys                              145150155160                                                                  TCCCGCCTCAACTGCTCCATTCCCGGCGATTATCCTTTCTACTTTAAT528                           SerArgLeuAsnCysSerIleProGlyAspTyrProPheTyrPheAsn                              165170175                                                                     GAAATCCAATCTGCCAGCAATCTGGTGGAGGGACAGTATGGCTCGATG576                           GluIleGlnSerAlaSerAsnLeuValGluGlyGlnTyrGlySerMet                              180185190                                                                     AGCTCGAAACTGATCTACGGAGTCTTCAACACGCCGAGCAACTCAATT624                           SerSerLysLeuIleTyrGlyValPheAsnThrProSerAsnSerIle                              195200205                                                                     CCCGGCTCAGCGGTTTGTGCCTTTGCCCTCCAGGACATTGCCGATACG672                           ProGlySerAlaValCysAlaPheAlaLeuGlnAspIleAlaAspThr                              210215220                                                                     TTTGAGGGTCAGTTCAAGGAGCAGACTGGCATCAACTCCAACTGGCTG720                           PheGluGlyGlnPheLysGluGlnThrGlyIleAsnSerAsnTrpLeu                              225230235240                                                                  CCAGTGAACAACGCCAAGGTACCCGATCCTCGACCCGGTTCCTGTCAC768                           ProValAsnAsnAlaLysValProAspProArgProGlySerCysHis                              245250255                                                                     AACGATTCGAGAGCGCTTCCGGATCCCACACTGAACTTCATCAAAACA816                           AsnAspSerArgAlaLeuProAspProThrLeuAsnPheIleLysThr                              260265270                                                                     CATTCGCTAATGGACGAGAATGTGCCGGCATTTTTCAGTCAACCGATT864                           HisSerLeuMetAspGluAsnValProAlaPhePheSerGlnProIle                              275280285                                                                     TTGGTCCGGACGAGCACAATATACCGCTTCACTCAAATCGCCGTAGAT912                           LeuValArgThrSerThrIleTyrArgPheThrGlnIleAlaValAsp                              290295300                                                                     GCGCAGATTAAAACTCCTGGCGGCAAGACATATGATGTTATCTTTGTG960                           AlaGlnIleLysThrProGlyGlyLysThrTyrAspValIlePheVal                              305310315320                                                                  GGCACAGATCATGGAAAGATTATTAAGTCAGTGAATGCTGAATCTGCC1008                          GlyThrAspHisGlyLysIleIleLysSerValAsnAlaGluSerAla                              325330335                                                                     GATTCAGCGGATAAAGTCACCTCCGTAGTCATCGAGGAGATCGATGTC1056                          AspSerAlaAspLysValThrSerValValIleGluGluIleAspVal                              340345350                                                                     CTGACCAAGAGTGAACCCATACGCAATCTGGAGATAGTCAGAACCATG1104                          LeuThrLysSerGluProIleArgAsnLeuGluIleValArgThrMet                              355360365                                                                     CAGTACGATCAACCCAAAGATGGCAGCTACGACGATGGTAAATTAATC1152                          GlnTyrAspGlnProLysAspGlySerTyrAspAspGlyLysLeuIle                              370375380                                                                     ATTGTGACGGACAGTCAGGTGGTAGCCATACAATTGCATCGTTGTCAC1200                          IleValThrAspSerGlnValValAlaIleGlnLeuHisArgCysHis                              385390395400                                                                  AATGACAAAATCACCAGCTGCAGCGAGTGCGTCGCATTGCAGGATCCG1248                          AsnAspLysIleThrSerCysSerGluCysValAlaLeuGlnAspPro                              405410415                                                                     TACTGCGCCTGGGACAAAATCGCTGGCAAGTGCCGTTCCCACGGCGCT1296                          TyrCysAlaTrpAspLysIleAlaGlyLysCysArgSerHisGlyAla                              420425430                                                                     CCCCGATGGCTAGAGGAGAACTATTTCTACCAGAATGTGGCCACTGGC1344                          ProArgTrpLeuGluGluAsnTyrPheTyrGlnAsnValAlaThrGly                              435440445                                                                     CAGCATGCGGCCTGCCCCTCAGGCAAAATCAATTCAAAGGATGCCAAC1392                          GlnHisAlaAlaCysProSerGlyLysIleAsnSerLysAspAlaAsn                              450455460                                                                     GCTGGGGAGCAGAAGGGCTTCCGCAACGACATGGACTTATTGGATTCG1440                          AlaGlyGluGlnLysGlyPheArgAsnAspMetAspLeuLeuAspSer                              465470475480                                                                  CGACGCCAGAGCAAGGATCAGGAAATAATCGACAATATTGATAAGAAC1488                          ArgArgGlnSerLysAspGlnGluIleIleAspAsnIleAspLysAsn                              485490495                                                                     TTTGAAGATATAATCAACGCCCAGTACACTGTGGAGACCCTCGTGATG1536                          PheGluAspIleIleAsnAlaGlnTyrThrValGluThrLeuValMet                              500505510                                                                     GCCGTTCTGGCCGGTTCGATCTTTTCGCTGCTGGTCGGCTTCTTTACA1584                          AlaValLeuAlaGlySerIlePheSerLeuLeuValGlyPhePheThr                              515520525                                                                     GGCTACTTCTGCGGTCGCCGTTGTCACAAGGACGAGGATGATAATCTG1632                          GlyTyrPheCysGlyArgArgCysHisLysAspGluAspAspAsnLeu                              530535540                                                                     CCGTATCCGGATACGGAGTACGAGTACTTCGAGCAGCGACAGAATGTC1680                          ProTyrProAspThrGluTyrGluTyrPheGluGlnArgGlnAsnVal                              545550555560                                                                  AATAGCTTCCCCTCGTCCTGTCGCATCCAGCAGGAGCCCAAGCTGCTG1728                          AsnSerPheProSerSerCysArgIleGlnGlnGluProLysLeuLeu                              565570575                                                                     CCCCAAGTGGAGGAGGTGACGTATGCGGACGCAGTGCTCCTGCCACAG1776                          ProGlnValGluGluValThrTyrAlaAspAlaValLeuLeuProGln                              580585590                                                                     CCTCCGCCGCCCAATAAGATGCACTCGCCGAAGAACACGCTGCGTAAG1824                          ProProProProAsnLysMetHisSerProLysAsnThrLeuArgLys                              595600605                                                                     CCCCCGATGCACCAGATGCACCAGGGTCCCAACTCGGAGACCCTCTTC1872                          ProProMetHisGlnMetHisGlnGlyProAsnSerGluThrLeuPhe                              610615620                                                                     CAGTTCCACGTGACGGCTACAACACCCAGCAGTCGTATCGTGGTCGCG1920                          GlnPheHisValThrAlaThrThrProSerSerArgIleValValAla                              625630635640                                                                  ACAACTTCGGAACACTGCGTTCCCACCAGGTGATGGGCGACAATTACAGG1970                        ThrThrSerGluHisCysValProThrArg                                                645650                                                                        CGCGGCGATGGCTTTTCCACCACCCGCAGCGTCAAGAAGGTTTACCTTTGAGACGGGAGT2030              GGGGCGGCTGAAACCAGTCAGGGACTAATTACCCAAAATATGGCTGTAAACAACACAAAC2090              ACACGTAACAGAAGTCTTGGTCGCGCAAGAAGACAGCCGCCCCGTCATGGCATTGTAACT2150              CAACACCGCTCGAATAGCCCCCAGCAGCAGCAGCAGCAGTCGCAGCAGCCGCACTCCAGT2210              TCGGGCTCCTCGCCCGTAATGTCCAACAGCAGCAGCAGTCCGGCTCCGCCCTCCAGCAGT2270              CCCAGTCCGCAGGAGAGCCCCAAGAACTGCAGCTACATCTACCGTGATTGATTGATATGC2330              AACACCAAATCGATGCCACTCATCCAGGCCCAGTCCACGCACGCCCAGCCACACTCACAC2390              CCGCACCCGCACCCGCTTCCGCCACCCGGTCCGACCACGCCCCCAGCACAGCCACGCGCC2450              AGAAGTCCAATGATCGGCAGGACATATGCCAAGTCCATGCCCGTGACACCAGTTCAACCG2510              CAATCGCCGCTGGCTGAGACGCCCTCCTATGAGCTCTACGAACGCCACTCGGATGCGGCC2570              ACCTTCCACTTTGGGGATGAGGACGATGACGATGATGATGAGCACGACCAGGAGGACACC2630              TCATCGCTGGCCATGATCACACCGCCGCCGCCCTACGACACTCCGCATCTGATTGCATCG2690              CCACCGCTGCCGCCGCCTCGTAGATTTCGCTTTGGCAACAGGGAGCTGTTCAGCATGAGT2750              CCAGCCGGAGGTGGAACCACGCCCACCGCCTCGGCAGGCCAACGCGGCAGCAGCGCCATC2810              ACGCCCACAAAGTTGAGTGCGGCGGCAGCGGCCATGTTTGCCGCACCCCAAATGGCCACC2870              CAACTCAACCGGAAGTGGGCTCATTTGCAAAGGAAGCGGCGCAGGCGCAACAGCAGCTCC2930              GGCGATTCTAAGGAGCTCGACAAACTGGTCCTGCAATCGGTCGACTGGGATGAGAATGAG2990              ATGTACTAGAACGCAAACCAACAATGAGATAGCAGAAACACTTTGATTCGGAATTTATAC3050              ACCTTTGCATATTTTGAATATGACTTCAATTTTAAAATGCGTAATTATGTTCTTATTTTT3110              TAAAGAACGCTTTAGAGAAGTTTTCTGCTACCTTAAATAGTACACACAACTCATATCTAA3170              CGTGGCGCTGCGATATAGGAATAACCACTCCCCCTTCCCTTAAACTTAAAGTAGCAATCG3230              AAAAGATCATTCATTAGCGACAGAAACTGGATGGGGATTTACTTACACACAAAAAGCCAG3290              AGAAGTTATACACGAAGTTTATAGTTATATAGCCTTTATACATACTCCCCGATCTGCTAA3350              GTATACACAAGCAAGCATAACATAACATACGTATATATGACTCTATATATACCAATAGAT3410              TTCATAGACGATTCACATGGATCGGCTACGCTAAATTAGAGCTGCAAAATGATATTGTTA3470              ATTACGATTAGAGAAAAAAAAAAAGGAATTCGATATCAAGCKTATCGATACCNTCGACCT3530              CGNNNNNGGGGCCCGGTACCCAATTCGCCC3560                                            (2) INFORMATION FOR SEQ ID NO:60:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 650 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: protein                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:60:                                      GluAspAspCysGlnAsnTyrIleArgIleMetValValProSerPro                              151015                                                                        GlyArgLeuPheValCysGlyThrAsnSerPheArgProMetCysAsn                              202530                                                                        ThrTyrIleIleSerAspSerAsnTyrThrLeuGluAlaThrLysAsn                              354045                                                                        GlyGlnAlaValCysProTyrAspProArgHisAsnSerThrSerVal                              505560                                                                        LeuAlaAspAsnGluLeuTyrSerGlyThrValAlaAspPheSerGly                              65707580                                                                      SerAspProIleIleTyrArgGluProLeuGlnThrGluGlnTyrAsp                              859095                                                                        SerLeuSerLeuAsnAlaProAsnPheValSerSerPheThrGlnGly                              100105110                                                                     AspPheValTyrPhePhePheArgGluThrAlaValGluPheIleAsn                              115120125                                                                     CysGlyLysAlaIleTyrSerArgValAlaArgValCysLysTrpAsp                              130135140                                                                     LysGlyGlyProHisArgPheArgAsnArgTrpThrSerPheLeuLys                              145150155160                                                                  SerArgLeuAsnCysSerIleProGlyAspTyrProPheTyrPheAsn                              165170175                                                                     GluIleGlnSerAlaSerAsnLeuValGluGlyGlnTyrGlySerMet                              180185190                                                                     SerSerLysLeuIleTyrGlyValPheAsnThrProSerAsnSerIle                              195200205                                                                     ProGlySerAlaValCysAlaPheAlaLeuGlnAspIleAlaAspThr                              210215220                                                                     PheGluGlyGlnPheLysGluGlnThrGlyIleAsnSerAsnTrpLeu                              225230235240                                                                  ProValAsnAsnAlaLysValProAspProArgProGlySerCysHis                              245250255                                                                     AsnAspSerArgAlaLeuProAspProThrLeuAsnPheIleLysThr                              260265270                                                                     HisSerLeuMetAspGluAsnValProAlaPhePheSerGlnProIle                              275280285                                                                     LeuValArgThrSerThrIleTyrArgPheThrGlnIleAlaValAsp                              290295300                                                                     AlaGlnIleLysThrProGlyGlyLysThrTyrAspValIlePheVal                              305310315320                                                                  GlyThrAspHisGlyLysIleIleLysSerValAsnAlaGluSerAla                              325330335                                                                     AspSerAlaAspLysValThrSerValValIleGluGluIleAspVal                              340345350                                                                     LeuThrLysSerGluProIleArgAsnLeuGluIleValArgThrMet                              355360365                                                                     GlnTyrAspGlnProLysAspGlySerTyrAspAspGlyLysLeuIle                              370375380                                                                     IleValThrAspSerGlnValValAlaIleGlnLeuHisArgCysHis                              385390395400                                                                  AsnAspLysIleThrSerCysSerGluCysValAlaLeuGlnAspPro                              405410415                                                                     TyrCysAlaTrpAspLysIleAlaGlyLysCysArgSerHisGlyAla                              420425430                                                                     ProArgTrpLeuGluGluAsnTyrPheTyrGlnAsnValAlaThrGly                              435440445                                                                     GlnHisAlaAlaCysProSerGlyLysIleAsnSerLysAspAlaAsn                              450455460                                                                     AlaGlyGluGlnLysGlyPheArgAsnAspMetAspLeuLeuAspSer                              465470475480                                                                  ArgArgGlnSerLysAspGlnGluIleIleAspAsnIleAspLysAsn                              485490495                                                                     PheGluAspIleIleAsnAlaGlnTyrThrValGluThrLeuValMet                              500505510                                                                     AlaValLeuAlaGlySerIlePheSerLeuLeuValGlyPhePheThr                              515520525                                                                     GlyTyrPheCysGlyArgArgCysHisLysAspGluAspAspAsnLeu                              530535540                                                                     ProTyrProAspThrGluTyrGluTyrPheGluGlnArgGlnAsnVal                              545550555560                                                                  AsnSerPheProSerSerCysArgIleGlnGlnGluProLysLeuLeu                              565570575                                                                     ProGlnValGluGluValThrTyrAlaAspAlaValLeuLeuProGln                              580585590                                                                     ProProProProAsnLysMetHisSerProLysAsnThrLeuArgLys                              595600605                                                                     ProProMetHisGlnMetHisGlnGlyProAsnSerGluThrLeuPhe                              610615620                                                                     GlnPheHisValThrAlaThrThrProSerSerArgIleValValAla                              625630635640                                                                  ThrThrSerGluHisCysValProThrArg                                                645650                                                                        (2) INFORMATION FOR SEQ ID NO:61:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 2670 base pairs                                                   (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: cDNA                                                      (ix) FEATURE:                                                                 (A) NAME/KEY: CDS                                                             (B) LOCATION: 268..2439                                                       (xi) SEQUENCE DESCRIPTION: SEQ ID NO:61:                                      GAAAATCGAACWCCGAATTGAATGAACWGCAAAACGCCAATTAGATAGTTGCAAGCCTAA60                TGCATTTCAGAKATTTNMMCGATGCGAAACAAGTTCCGCCACGAAAGTGAACAGTGGTAA120               AATGCCCAAGAATCTCGAGCGGAAACACCAAACACAAAAGAACAAGCAACCGCCTCTCAC180               TCGCTCTTGCACTTTAATCCAATTGAGGTTGGTGGGGTCGCATTCGCCCCCCGGTCGACC240               ACCCCTCTCGCTCGCACCGCCCTCGCAATGTCTCTTCTACAGCTATCGCCGCTC294                     MetSerLeuLeuGlnLeuSerProLeu                                                   15                                                                            CTCGCACTCCTGCTACTCCTCTGCAGTAGTGTGAGCGAGACGGCTGCG342                           LeuAlaLeuLeuLeuLeuLeuCysSerSerValSerGluThrAlaAla                              10152025                                                                      GACTACGAGAACACCTGGAACTTCTACTACGAGCGTCCCTGTTGCACT390                           AspTyrGluAsnThrTrpAsnPheTyrTyrGluArgProCysCysThr                              303540                                                                        GGAAACGATCAGGGGAACAACAATTACGGAAAACACGGCGCAGATCAT438                           GlyAsnAspGlnGlyAsnAsnAsnTyrGlyLysHisGlyAlaAspHis                              455055                                                                        GTGCGGGAGTTCAACTGCGGCAAGCTGTACTATCGTACATTCCATATG486                           ValArgGluPheAsnCysGlyLysLeuTyrTyrArgThrPheHisMet                              606570                                                                        AACGAAGATCGAGATACGCTCTATGTGGGAGCCATGGATCGCGTATTC534                           AsnGluAspArgAspThrLeuTyrValGlyAlaMetAspArgValPhe                              758085                                                                        CGTGTGAACCTGCAGAATATCTCCTCATCCAATTGTAATCGGGATGCG582                           ArgValAsnLeuGlnAsnIleSerSerSerAsnCysAsnArgAspAla                              9095100105                                                                    ATCAACTTGGAGCCAACACGGGATGATGTGGTTAGCTGCGTCTCCAAA630                           IleAsnLeuGluProThrArgAspAspValValSerCysValSerLys                              110115120                                                                     GGCAAAAGTCAGATCTTCGACTGCAAGAACCATGTGCGTGTCATCCAG678                           GlyLysSerGlnIlePheAspCysLysAsnHisValArgValIleGln                              125130135                                                                     TCAATGGACCAGGGGGATAGGCTCTATGTATGCGGCACCAACGCCCAC726                           SerMetAspGlnGlyAspArgLeuTyrValCysGlyThrAsnAlaHis                              140145150                                                                     AATCCCAAGGATTATGTTATCTATGCGAATCTAACCCACCTGCCGCGC774                           AsnProLysAspTyrValIleTyrAlaAsnLeuThrHisLeuProArg                              155160165                                                                     TCGGAATATGTGATTGGCGTGGGTCTGGGCATTGCCAAGTGCCCCTAC822                           SerGluTyrValIleGlyValGlyLeuGlyIleAlaLysCysProTyr                              170175180185                                                                  GATCCCCTCGACAACTCAACTGCGATTTATGTGGAGAATGGCAATCCG870                           AspProLeuAspAsnSerThrAlaIleTyrValGluAsnGlyAsnPro                              190195200                                                                     GGTGGTCTGCCCGGTTTGTACTCCGGCACCAATGCGGAGTTCACCAAG918                           GlyGlyLeuProGlyLeuTyrSerGlyThrAsnAlaGluPheThrLys                              205210215                                                                     GCGGATACGGTTATTTTCCGCACTGATCTGTATAATACTTCGGCTAAA966                           AlaAspThrValIlePheArgThrAspLeuTyrAsnThrSerAlaLys                              220225230                                                                     CGTTTGGAATATAAATTCAAGAGGACTCTGAAATACGACTCCAAGTGG1014                          ArgLeuGluTyrLysPheLysArgThrLeuLysTyrAspSerLysTrp                              235240245                                                                     TTGGACAAACCAAACTTTGTCGGCTCCTTTGATATTGGGGAGTACGTG1062                          LeuAspLysProAsnPheValGlySerPheAspIleGlyGluTyrVal                              250255260265                                                                  TATTTCTTTTTCCGTGAAACCGCCGTGGAATACATCAACTGCGGCAAG1110                          TyrPhePhePheArgGluThrAlaValGluTyrIleAsnCysGlyLys                              270275280                                                                     GCTGTCTATTCGCGCATCGCACGGGTGTGCAAGAAGGATGTGGGTGGA1158                          AlaValTyrSerArgIleAlaArgValCysLysLysAspValGlyGly                              285290295                                                                     AAGAATCTGCTGGCCCACAACTGGGCCACCTACCTGAAGGCCAGACTC1206                          LysAsnLeuLeuAlaHisAsnTrpAlaThrTyrLeuLysAlaArgLeu                              300305310                                                                     AACTGCAGCATCTCCGGCGAATTTCCGTTCTATTTCAACGAGATCCAA1254                          AsnCysSerIleSerGlyGluPheProPheTyrPheAsnGluIleGln                              315320325                                                                     TCGGTCTACCAGCTGCCCTCCGATAAGAGTCGATTCTTCGCCACATTC1302                          SerValTyrGlnLeuProSerAspLysSerArgPhePheAlaThrPhe                              330335340345                                                                  ACGACGAGCACTAATGGCCTGATTGGATCTGCCGTATGCAGTTTCCAC1350                          ThrThrSerThrAsnGlyLeuIleGlySerAlaValCysSerPheHis                              350355360                                                                     ATTAACGAGATTCAGGCTGCCTTCAATGGCAAATTCAAGGAGCAATCT1398                          IleAsnGluIleGlnAlaAlaPheAsnGlyLysPheLysGluGlnSer                              365370375                                                                     TCATCGAATTCCGCATGGCTGCCGGTGCTTAACTCCCGGGTGCCGGAA1446                          SerSerAsnSerAlaTrpLeuProValLeuAsnSerArgValProGlu                              380385390                                                                     CCACGGCCGGGTACATGTGTCAACGATACATCAAACCTGCCCGATACC1494                          ProArgProGlyThrCysValAsnAspThrSerAsnLeuProAspThr                              395400405                                                                     GTACTGAATTTCATCAGATCCCATCCACTTATGGACAAAGCCGTAAAT1542                          ValLeuAsnPheIleArgSerHisProLeuMetAspLysAlaValAsn                              410415420425                                                                  CACGAGCACAACAATCCAGTCTATTATAAAAGGGATTTGGTCTTCACC1590                          HisGluHisAsnAsnProValTyrTyrLysArgAspLeuValPheThr                              430435440                                                                     AAGCTCGTCGTTGACAAAATTCGCATTGACATCCTCAACCAGGAATAC1638                          LysLeuValValAspLysIleArgIleAspIleLeuAsnGlnGluTyr                              445450455                                                                     ATTGTGTACTATGTGGGCACCAATCTGGGTCGCATTTACAAAATCGTG1686                          IleValTyrTyrValGlyThrAsnLeuGlyArgIleTyrLysIleVal                              460465470                                                                     CAGTACTACCGTAACGGAGAGTCGCTGTCCAAGCTTCTGGATATCTTC1734                          GlnTyrTyrArgAsnGlyGluSerLeuSerLysLeuLeuAspIlePhe                              475480485                                                                     GAGGTGGCTCCAAACGAGGCCATCCAAGTGATGGAAATCAGCCAGACA1782                          GluValAlaProAsnGluAlaIleGlnValMetGluIleSerGlnThr                              490495500505                                                                  CGTAAGAGCCTCTACATTGGCACCGATCATCGCATCAAGCAAATCGAC1830                          ArgLysSerLeuTyrIleGlyThrAspHisArgIleLysGlnIleAsp                              510515520                                                                     CTGGCCATGTGCAATCGCCGTTACGACAACTGCTTCCGCTGCGTCCGT1878                          LeuAlaMetCysAsnArgArgTyrAspAsnCysPheArgCysValArg                              525530535                                                                     GATCCCTACTGCGGCTGGGATAAGGAGGCCAATACGTGCCGACCGTAC1926                          AspProTyrCysGlyTrpAspLysGluAlaAsnThrCysArgProTyr                              540545550                                                                     GAGCTGGATTTACTGCAGGATGTGGCCAATGAAACGAGTGACATTTGC1974                          GluLeuAspLeuLeuGlnAspValAlaAsnGluThrSerAspIleCys                              555560565                                                                     GATTCGAGTGTGCTGAAAAAGAAGATTGTGGTGACCTATGGCCAGAGT2022                          AspSerSerValLeuLysLysLysIleValValThrTyrGlyGlnSer                              570575580585                                                                  GTACATCTGGGCTGTTTCGTCAAAATACCCGAAGTGCTGAAGAATGAG2070                          ValHisLeuGlyCysPheValLysIleProGluValLeuLysAsnGlu                              590595600                                                                     CAAGTGACCTGGTATCATCACTCCAAGGACAAGGGACGCTACGAGATT2118                          GlnValThrTrpTyrHisHisSerLysAspLysGlyArgTyrGluIle                              605610615                                                                     CGTTACTCGCCGACCAAATACATTGAGACCACCGAACGTGGCCTGGTT2166                          ArgTyrSerProThrLysTyrIleGluThrThrGluArgGlyLeuVal                              620625630                                                                     GTGGTTTCCGTGAACGAAGCCGATGGTGGTCGGTACGATTGCCATTTG2214                          ValValSerValAsnGluAlaAspGlyGlyArgTyrAspCysHisLeu                              635640645                                                                     GGCGGCTCGCTTTTGTGCAGCTACAACATTACAGTGGATGCCCACAGA2262                          GlyGlySerLeuLeuCysSerTyrAsnIleThrValAspAlaHisArg                              650655660665                                                                  TGCACTCCGCCGAACAAGAGTAATGACTATCAGAAAATCTACTCGGAC2310                          CysThrProProAsnLysSerAsnAspTyrGlnLysIleTyrSerAsp                              670675680                                                                     TGGTGCCACGAGTTCGAGAAATACAAAACAGCAATGAAGTCCTGGGAA2358                          TrpCysHisGluPheGluLysTyrLysThrAlaMetLysSerTrpGlu                              685690695                                                                     AAGAAGCAAGGCCAATGCTCGACACGGCAGAACTTCAGCTGCAATCAG2406                          LysLysGlnGlyGlnCysSerThrArgGlnAsnPheSerCysAsnGln                              700705710                                                                     CATCCGAATGAGATTTTCCGTAAGCCCAATGTCTGATATCACGAAGAGAGTAT2459                     HisProAsnGluIlePheArgLysProAsnVal                                             715720                                                                        CGCCCTCAAAATGCCGTCATCGTCGTCCAATCAATTTTAGTTAATCGAAAGCGAAGAGGA2519              TAATAACAGTGCGGAATAGAAAGCCCAGGACGAGAAGAACTCATTATAATCATTATTATC2579              AGCGACATCATCATAGACATACTTTCTTCAGCAATGAACAGAAAACTCTTCCTAAAGGAT2639              TATGCATTTACCGAAGCATTTACAATGCATC2670                                           (2) INFORMATION FOR SEQ ID NO:62:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 724 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: protein                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:62:                                      MetSerLeuLeuGlnLeuSerProLeuLeuAlaLeuLeuLeuLeuLeu                              151015                                                                        CysSerSerValSerGluThrAlaAlaAspTyrGluAsnThrTrpAsn                              202530                                                                        PheTyrTyrGluArgProCysCysThrGlyAsnAspGlnGlyAsnAsn                              354045                                                                        AsnTyrGlyLysHisGlyAlaAspHisValArgGluPheAsnCysGly                              505560                                                                        LysLeuTyrTyrArgThrPheHisMetAsnGluAspArgAspThrLeu                              65707580                                                                      TyrValGlyAlaMetAspArgValPheArgValAsnLeuGlnAsnIle                              859095                                                                        SerSerSerAsnCysAsnArgAspAlaIleAsnLeuGluProThrArg                              100105110                                                                     AspAspValValSerCysValSerLysGlyLysSerGlnIlePheAsp                              115120125                                                                     CysLysAsnHisValArgValIleGlnSerMetAspGlnGlyAspArg                              130135140                                                                     LeuTyrValCysGlyThrAsnAlaHisAsnProLysAspTyrValIle                              145150155160                                                                  TyrAlaAsnLeuThrHisLeuProArgSerGluTyrValIleGlyVal                              165170175                                                                     GlyLeuGlyIleAlaLysCysProTyrAspProLeuAspAsnSerThr                              180185190                                                                     AlaIleTyrValGluAsnGlyAsnProGlyGlyLeuProGlyLeuTyr                              195200205                                                                     SerGlyThrAsnAlaGluPheThrLysAlaAspThrValIlePheArg                              210215220                                                                     ThrAspLeuTyrAsnThrSerAlaLysArgLeuGluTyrLysPheLys                              225230235240                                                                  ArgThrLeuLysTyrAspSerLysTrpLeuAspLysProAsnPheVal                              245250255                                                                     GlySerPheAspIleGlyGluTyrValTyrPhePhePheArgGluThr                              260265270                                                                     AlaValGluTyrIleAsnCysGlyLysAlaValTyrSerArgIleAla                              275280285                                                                     ArgValCysLysLysAspValGlyGlyLysAsnLeuLeuAlaHisAsn                              290295300                                                                     TrpAlaThrTyrLeuLysAlaArgLeuAsnCysSerIleSerGlyGlu                              305310315320                                                                  PheProPheTyrPheAsnGluIleGlnSerValTyrGlnLeuProSer                              325330335                                                                     AspLysSerArgPhePheAlaThrPheThrThrSerThrAsnGlyLeu                              340345350                                                                     IleGlySerAlaValCysSerPheHisIleAsnGluIleGlnAlaAla                              355360365                                                                     PheAsnGlyLysPheLysGluGlnSerSerSerAsnSerAlaTrpLeu                              370375380                                                                     ProValLeuAsnSerArgValProGluProArgProGlyThrCysVal                              385390395400                                                                  AsnAspThrSerAsnLeuProAspThrValLeuAsnPheIleArgSer                              405410415                                                                     HisProLeuMetAspLysAlaValAsnHisGluHisAsnAsnProVal                              420425430                                                                     TyrTyrLysArgAspLeuValPheThrLysLeuValValAspLysIle                              435440445                                                                     ArgIleAspIleLeuAsnGlnGluTyrIleValTyrTyrValGlyThr                              450455460                                                                     AsnLeuGlyArgIleTyrLysIleValGlnTyrTyrArgAsnGlyGlu                              465470475480                                                                  SerLeuSerLysLeuLeuAspIlePheGluValAlaProAsnGluAla                              485490495                                                                     IleGlnValMetGluIleSerGlnThrArgLysSerLeuTyrIleGly                              500505510                                                                     ThrAspHisArgIleLysGlnIleAspLeuAlaMetCysAsnArgArg                              515520525                                                                     TyrAspAsnCysPheArgCysValArgAspProTyrCysGlyTrpAsp                              530535540                                                                     LysGluAlaAsnThrCysArgProTyrGluLeuAspLeuLeuGlnAsp                              545550555560                                                                  ValAlaAsnGluThrSerAspIleCysAspSerSerValLeuLysLys                              565570575                                                                     LysIleValValThrTyrGlyGlnSerValHisLeuGlyCysPheVal                              580585590                                                                     LysIleProGluValLeuLysAsnGluGlnValThrTrpTyrHisHis                              595600605                                                                     SerLysAspLysGlyArgTyrGluIleArgTyrSerProThrLysTyr                              610615620                                                                     IleGluThrThrGluArgGlyLeuValValValSerValAsnGluAla                              625630635640                                                                  AspGlyGlyArgTyrAspCysHisLeuGlyGlySerLeuLeuCysSer                              645650655                                                                     TyrAsnIleThrValAspAlaHisArgCysThrProProAsnLysSer                              660665670                                                                     AsnAspTyrGlnLysIleTyrSerAspTrpCysHisGluPheGluLys                              675680685                                                                     TyrLysThrAlaMetLysSerTrpGluLysLysGlnGlyGlnCysSer                              690695700                                                                     ThrArgGlnAsnPheSerCysAsnGlnHisProAsnGluIlePheArg                              705710715720                                                                  LysProAsnVal                                                                  (2) INFORMATION FOR SEQ ID NO:63:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 2504 base pairs                                                   (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: cDNA                                                      (ix) FEATURE:                                                                 (A) NAME/KEY: CDS                                                             (B) LOCATION: 355..2493                                                       (xi) SEQUENCE DESCRIPTION: SEQ ID NO:63:                                      GGCCGGTCGACCACGAGCGAAGTTTAGTATCAAGTTGAGAGTTTGTTTGGAGCGTAGTTT60                ACGGAGCGTACATTTAAATTTGCGGACAAATCGTGTTTTGGTGCTTCTCTGTGGATTGTT120               GTGTTCTTGAAGATGCTTCCCTTGGTTTTCGGATAAGCTTTCCTGTGGATTGTTGTGTTC180               TTGAAGATGCTTCCCTTGGTTTTCGGATAAGCTTTCCAGCGTGGTTTCAGCCTCGGCTTG240               TTTGGACCCCGACATAATCTTCGAACTACAATGAAGAGGAAATTTTGAAACGCGTTTCAG300               ACGCGTACAATCGACAAAATGTTTGGTTTCCAATTGATCTTGCAATGTAGCTACATG357                  Met                                                                           GTGGTGAAGATCTTGGTTTGGTCGATATGTCTGATAGCGCTGTGTCAT405                           ValValLysIleLeuValTrpSerIleCysLeuIleAlaLeuCysHis                              51015                                                                         GCTTGGATGCCGGATAGTTCTTCCAAATTAATAAACCATTTTAAATCA453                           AlaTrpMetProAspSerSerSerLysLeuIleAsnHisPheLysSer                              202530                                                                        GTTGAAAGTAAAAGCTTTACCGGGAACGCCACGTTCCCTGATCACTTT501                           ValGluSerLysSerPheThrGlyAsnAlaThrPheProAspHisPhe                              354045                                                                        ATTGTCTTGAATCAAGACGAAACTTCGATATTAGTAGGCGGTAGAAAT549                           IleValLeuAsnGlnAspGluThrSerIleLeuValGlyGlyArgAsn                              50556065                                                                      AGGGTTTACAATTTAAGTATATTCGACCTCAGTGAGCGTAAAGGGGGG597                           ArgValTyrAsnLeuSerIlePheAspLeuSerGluArgLysGlyGly                              707580                                                                        CGAATCGACTGGCCATCGTCCGATGCACATGGCCAGTTGTGTATATTG645                           ArgIleAspTrpProSerSerAspAlaHisGlyGlnLeuCysIleLeu                              859095                                                                        AAAGGGAAAACGGACGACGACTGCCAAAATTACATTAGAATACTGTAC693                           LysGlyLysThrAspAspAspCysGlnAsnTyrIleArgIleLeuTyr                              100105110                                                                     TCTTCAGAACCGGGGAAATTAGTTATTTGCGGGACCAATTCGTACAAA741                           SerSerGluProGlyLysLeuValIleCysGlyThrAsnSerTyrLys                              115120125                                                                     CCCCTCTGTCGGACGTACGCATTTAAGGAGGGAAAGTACCTGGTTGAG789                           ProLeuCysArgThrTyrAlaPheLysGluGlyLysTyrLeuValGlu                              130135140145                                                                  AAAGAAGTAGAAGGGATAGGCTTGTGTCCATACAATCCGGAACACAAC837                           LysGluValGluGlyIleGlyLeuCysProTyrAsnProGluHisAsn                              150155160                                                                     AGCACATCTGTCTCCTACAATGGCCAATTATTTTCAGCGACGGTCGCC885                           SerThrSerValSerTyrAsnGlyGlnLeuPheSerAlaThrValAla                              165170175                                                                     GACTTTTCCGGGGGCGACCCTCTCATATACAGGGAGCCCCAGCGCACC933                           AspPheSerGlyGlyAspProLeuIleTyrArgGluProGlnArgThr                              180185190                                                                     GAACTCTCAGATCTCAAACAACTGAACGCACCGAATTTCGTAAACTCG981                           GluLeuSerAspLeuLysGlnLeuAsnAlaProAsnPheValAsnSer                              195200205                                                                     GTGGCCTATGGCGACTACATATTCTTCTTCTACCGTGAAACCGCCGTC1029                          ValAlaTyrGlyAspTyrIlePhePhePheTyrArgGluThrAlaVal                              210215220225                                                                  GAGTACATGAACTGCGGAAAAGTCATCTACTCGCGGGTCGCCAGGGTG1077                          GluTyrMetAsnCysGlyLysValIleTyrSerArgValAlaArgVal                              230235240                                                                     TGCAAGGACGACAAAGGGGGCCCTCACCAGTCACGCGACCGCTGGACG1125                          CysLysAspAspLysGlyGlyProHisGlnSerArgAspArgTrpThr                              245250255                                                                     TCGTTCCTCAAAGCACGTCTCAATTGTTCAATTCCCGGCGAGTACCCC1173                          SerPheLeuLysAlaArgLeuAsnCysSerIleProGlyGluTyrPro                              260265270                                                                     TTTTACTTTGATGAAATCCAATCAACAAGTGATATAGTCGAGGGTCGG1221                          PheTyrPheAspGluIleGlnSerThrSerAspIleValGluGlyArg                              275280285                                                                     TACAATTCCGACGACAGCAAAAAGATCATTTATGGAATCCTCACAACT1269                          TyrAsnSerAspAspSerLysLysIleIleTyrGlyIleLeuThrThr                              290295300305                                                                  CCAGTTAATGCCATCGGCGGCTCGGCCATTTGCGCGTATCAAATGGCC1317                          ProValAsnAlaIleGlyGlySerAlaIleCysAlaTyrGlnMetAla                              310315320                                                                     GACATCTTGCGCGTGTTTGAAGGGAGCTTCAAGCACCAAGAGACGATC1365                          AspIleLeuArgValPheGluGlySerPheLysHisGlnGluThrIle                              325330335                                                                     AACTCGAACTGGCTCCCCGTGCCCCAGAACCTAGTCCCTGAACCCAGG1413                          AsnSerAsnTrpLeuProValProGlnAsnLeuValProGluProArg                              340345350                                                                     CCCGGGCAGTGCGTACGCGACAGCAGGATCCTGCCCGACAAGAACGTC1461                          ProGlyGlnCysValArgAspSerArgIleLeuProAspLysAsnVal                              355360365                                                                     AACTTTATTAAGACCCACTCTTTGATGGAGGACGTTCCGGCTCTTTTC1509                          AsnPheIleLysThrHisSerLeuMetGluAspValProAlaLeuPhe                              370375380385                                                                  GGAAAACCAGTTCTGGTCCGAGTGAGTCTGCAGTATCGGTTTACAGCC1557                          GlyLysProValLeuValArgValSerLeuGlnTyrArgPheThrAla                              390395400                                                                     ATAACAGTGGATCCACAAGTGAAAACAATCAATAATCAGTATCTCGAT1605                          IleThrValAspProGlnValLysThrIleAsnAsnGlnTyrLeuAsp                              405410415                                                                     GTTTTGTATATCGGAACAGATGATGGGAAGGTACTAAAAGCTGTTAAT1653                          ValLeuTyrIleGlyThrAspAspGlyLysValLeuLysAlaValAsn                              420425430                                                                     ATACCAAAGCGACACGCTAAAGCGTTGTTATATCGAAAATACCGTACA1701                          IleProLysArgHisAlaLysAlaLeuLeuTyrArgLysTyrArgThr                              435440445                                                                     TCCGTACATCCGCACGGAGCTCCCGTAAAACAGCTGAAGATCGCTCCC1749                          SerValHisProHisGlyAlaProValLysGlnLeuLysIleAlaPro                              450455460465                                                                  GGTTATGGCAAAGTTGTGGTGGTCGGGAAAGACGAAATCAGACTTGCT1797                          GlyTyrGlyLysValValValValGlyLysAspGluIleArgLeuAla                              470475480                                                                     AATCTCAACCATTGTGCAAGCAAAACGCGGTGCAAGGACTGTGTGGAA1845                          AsnLeuAsnHisCysAlaSerLysThrArgCysLysAspCysValGlu                              485490495                                                                     CTGCAAGACCCACATTGCGCCTGGGACGCCAAACAAAACCTGTGTGTC1893                          LeuGlnAspProHisCysAlaTrpAspAlaLysGlnAsnLeuCysVal                              500505510                                                                     AGCATTGACACCGTCACTTCGTATCGCTTCCTGATCCAGGACGTAGTT1941                          SerIleAspThrValThrSerTyrArgPheLeuIleGlnAspValVal                              515520525                                                                     CGCGGCGACGACAACAAATGTTGGTCGCCGCAAACAGACAAAAAGACT1989                          ArgGlyAspAspAsnLysCysTrpSerProGlnThrAspLysLysThr                              530535540545                                                                  GTGATTAAGAATAAGCCCAGCGAGGTTGAGAACGAGATTACGAACTCC2037                          ValIleLysAsnLysProSerGluValGluAsnGluIleThrAsnSer                              550555560                                                                     ATTGACGAAAAGGATCTCGATTCAAGCGATCCGCTCATCAAAACTGGT2085                          IleAspGluLysAspLeuAspSerSerAspProLeuIleLysThrGly                              565570575                                                                     CTCGATGACGATTCCGATTGTGATCCAGTCAGCGAGAACAGCATAGGC2133                          LeuAspAspAspSerAspCysAspProValSerGluAsnSerIleGly                              580585590                                                                     GGATGCGCCGTCCGCCAGCAACTTGTTATATACACAGCTGGGACTCTA2181                          GlyCysAlaValArgGlnGlnLeuValIleTyrThrAlaGlyThrLeu                              595600605                                                                     CACATTGTCGTGGTCGTCGTCAGCATCGTGGGTTTATTTTCTTGGCTT2229                          HisIleValValValValValSerIleValGlyLeuPheSerTrpLeu                              610615620625                                                                  TATAGCGGGTTATCTGTTTTCGCAAAATTTCACTCGGATTCGCAATAT2277                          TyrSerGlyLeuSerValPheAlaLysPheHisSerAspSerGlnTyr                              630635640                                                                     CCTGAGGCGCCGTTTATAGAGCAGCACAATCATTTGGAAAGATTAAGC2325                          ProGluAlaProPheIleGluGlnHisAsnHisLeuGluArgLeuSer                              645650655                                                                     GCCAACCAGACGGGGTATTTGACTCCGAGGGCCAATAAAGCGGTCAAT2373                          AlaAsnGlnThrGlyTyrLeuThrProArgAlaAsnLysAlaValAsn                              660665670                                                                     TTGGTGGTGAAGGTGTCTAGTAGCACGCCGCGGCCGAAAAAGGACAAT2421                          LeuValValLysValSerSerSerThrProArgProLysLysAspAsn                              675680685                                                                     CTCGATGTCAGCAAAGACTTGAACATTGCGAGTGACGGGACTTTGCAA2469                          LeuAspValSerLysAspLeuAsnIleAlaSerAspGlyThrLeuGln                              690695700705                                                                  AAAATCAAGAAGACTTACATTTAGTGCGACTTTTT2504                                       LysIleLysLysThrTyrIle                                                         710                                                                           (2) INFORMATION FOR SEQ ID NO:64:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 712 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: protein                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:64:                                      MetValValLysIleLeuValTrpSerIleCysLeuIleAlaLeuCys                              151015                                                                        HisAlaTrpMetProAspSerSerSerLysLeuIleAsnHisPheLys                              202530                                                                        SerValGluSerLysSerPheThrGlyAsnAlaThrPheProAspHis                              354045                                                                        PheIleValLeuAsnGlnAspGluThrSerIleLeuValGlyGlyArg                              505560                                                                        AsnArgValTyrAsnLeuSerIlePheAspLeuSerGluArgLysGly                              65707580                                                                      GlyArgIleAspTrpProSerSerAspAlaHisGlyGlnLeuCysIle                              859095                                                                        LeuLysGlyLysThrAspAspAspCysGlnAsnTyrIleArgIleLeu                              100105110                                                                     TyrSerSerGluProGlyLysLeuValIleCysGlyThrAsnSerTyr                              115120125                                                                     LysProLeuCysArgThrTyrAlaPheLysGluGlyLysTyrLeuVal                              130135140                                                                     GluLysGluValGluGlyIleGlyLeuCysProTyrAsnProGluHis                              145150155160                                                                  AsnSerThrSerValSerTyrAsnGlyGlnLeuPheSerAlaThrVal                              165170175                                                                     AlaAspPheSerGlyGlyAspProLeuIleTyrArgGluProGlnArg                              180185190                                                                     ThrGluLeuSerAspLeuLysGlnLeuAsnAlaProAsnPheValAsn                              195200205                                                                     SerValAlaTyrGlyAspTyrIlePhePhePheTyrArgGluThrAla                              210215220                                                                     ValGluTyrMetAsnCysGlyLysValIleTyrSerArgValAlaArg                              225230235240                                                                  ValCysLysAspAspLysGlyGlyProHisGlnSerArgAspArgTrp                              245250255                                                                     ThrSerPheLeuLysAlaArgLeuAsnCysSerIleProGlyGluTyr                              260265270                                                                     ProPheTyrPheAspGluIleGlnSerThrSerAspIleValGluGly                              275280285                                                                     ArgTyrAsnSerAspAspSerLysLysIleIleTyrGlyIleLeuThr                              290295300                                                                     ThrProValAsnAlaIleGlyGlySerAlaIleCysAlaTyrGlnMet                              305310315320                                                                  AlaAspIleLeuArgValPheGluGlySerPheLysHisGlnGluThr                              325330335                                                                     IleAsnSerAsnTrpLeuProValProGlnAsnLeuValProGluPro                              340345350                                                                     ArgProGlyGlnCysValArgAspSerArgIleLeuProAspLysAsn                              355360365                                                                     ValAsnPheIleLysThrHisSerLeuMetGluAspValProAlaLeu                              370375380                                                                     PheGlyLysProValLeuValArgValSerLeuGlnTyrArgPheThr                              385390395400                                                                  AlaIleThrValAspProGlnValLysThrIleAsnAsnGlnTyrLeu                              405410415                                                                     AspValLeuTyrIleGlyThrAspAspGlyLysValLeuLysAlaVal                              420425430                                                                     AsnIleProLysArgHisAlaLysAlaLeuLeuTyrArgLysTyrArg                              435440445                                                                     ThrSerValHisProHisGlyAlaProValLysGlnLeuLysIleAla                              450455460                                                                     ProGlyTyrGlyLysValValValValGlyLysAspGluIleArgLeu                              465470475480                                                                  AlaAsnLeuAsnHisCysAlaSerLysThrArgCysLysAspCysVal                              485490495                                                                     GluLeuGlnAspProHisCysAlaTrpAspAlaLysGlnAsnLeuCys                              500505510                                                                     ValSerIleAspThrValThrSerTyrArgPheLeuIleGlnAspVal                              515520525                                                                     ValArgGlyAspAspAsnLysCysTrpSerProGlnThrAspLysLys                              530535540                                                                     ThrValIleLysAsnLysProSerGluValGluAsnGluIleThrAsn                              545550555560                                                                  SerIleAspGluLysAspLeuAspSerSerAspProLeuIleLysThr                              565570575                                                                     GlyLeuAspAspAspSerAspCysAspProValSerGluAsnSerIle                              580585590                                                                     GlyGlyCysAlaValArgGlnGlnLeuValIleTyrThrAlaGlyThr                              595600605                                                                     LeuHisIleValValValValValSerIleValGlyLeuPheSerTrp                              610615620                                                                     LeuTyrSerGlyLeuSerValPheAlaLysPheHisSerAspSerGln                              625630635640                                                                  TyrProGluAlaProPheIleGluGlnHisAsnHisLeuGluArgLeu                              645650655                                                                     SerAlaAsnGlnThrGlyTyrLeuThrProArgAlaAsnLysAlaVal                              660665670                                                                     AsnLeuValValLysValSerSerSerThrProArgProLysLysAsp                              675680685                                                                     AsnLeuAspValSerLysAspLeuAsnIleAlaSerAspGlyThrLeu                              690695700                                                                     GlnLysIleLysLysThrTyrIle                                                      705710                                                                        (2) INFORMATION FOR SEQ ID NO:65:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 369 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: cDNA                                                      (ix) FEATURE:                                                                 (A) NAME/KEY: CDS                                                             (B) LOCATION: 1..369                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:65:                                      ATGATTTATTTATACACGGCGGATAACGTAATTCCAAAAGATGGTTTA48                            MetIleTyrLeuTyrThrAlaAspAsnValIleProLysAspGlyLeu                              151015                                                                        CAAGGAGCATTTGTCGATAAAGACGGTACTTATGACAAAGTTTACATT96                            GlnGlyAlaPheValAspLysAspGlyThrTyrAspLysValTyrIle                              202530                                                                        CTTTTCACTGTTACTATCGGCTCAAAGAGAATTGTTAAAATTCCGTAT144                           LeuPheThrValThrIleGlySerLysArgIleValLysIleProTyr                              354045                                                                        ATAGCACAAATGTGCTTAAACGACGAATGTGGTCCATCATCATTGTCT192                           IleAlaGlnMetCysLeuAsnAspGluCysGlyProSerSerLeuSer                              505560                                                                        AGTCATAGATGGTCGACGTTGCTCAAAGTCGAATTAGAATGTGACATC240                           SerHisArgTrpSerThrLeuLeuLysValGluLeuGluCysAspIle                              65707580                                                                      GACGGAAGAAGTTATAGTCAAATTAATCATTCTAAAACTATAAAACAG288                           AspGlyArgSerTyrSerGlnIleAsnHisSerLysThrIleLysGln                              859095                                                                        ATAATGATACGATACTATATGTATTCTTTGATAGTCCTTTTCCAAGTC336                           IleMetIleArgTyrTyrMetTyrSerLeuIleValLeuPheGlnVal                              100105110                                                                     CGCATTATGTACCTATTCTATGAATACCATTAA369                                          ArgIleMetTyrLeuPheTyrGluTyrHis                                                115120                                                                        (2) INFORMATION FOR SEQ ID NO:66:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 122 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: protein                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:66:                                      MetIleTyrLeuTyrThrAlaAspAsnValIleProLysAspGlyLeu                              151015                                                                        GlnGlyAlaPheValAspLysAspGlyThrTyrAspLysValTyrIle                              202530                                                                        LeuPheThrValThrIleGlySerLysArgIleValLysIleProTyr                              354045                                                                        IleAlaGlnMetCysLeuAsnAspGluCysGlyProSerSerLeuSer                              505560                                                                        SerHisArgTrpSerThrLeuLeuLysValGluLeuGluCysAspIle                              65707580                                                                      AspGlyArgSerTyrSerGlnIleAsnHisSerLysThrIleLysGln                              859095                                                                        IleMetIleArgTyrTyrMetTyrSerLeuIleValLeuPheGlnVal                              100105110                                                                     ArgIleMetTyrLeuPheTyrGluTyrHis                                                115120                                                                        (2) INFORMATION FOR SEQ ID NO:67:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:67:                                      AspCysGlnAsnTyrIle                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:68:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ68                                           /note= "Xaa denotes N or G at residue #4; and A or S                          at residue #5"                                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:68:                                      CysGlyThrXaaXaaXaaXaaPro                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:69:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ69                                           /note= "Xaa denotes S or C at residue #3"                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:69:                                      GlyXaaXaaProTyrAspPro                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:70:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ70                                           /note= "Xaa denotes V, N or A"                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:70:                                      LeuTyrSerGlyThrXaaAla                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:71:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:71:                                      LeuAsnAlaProAsnPheVal                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:72:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ72                                           /note= "Xaa denotes V or I"                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:72:                                      ArgXaaAlaArgValCysLys                                                         (2) INFORMATION FOR SEQ ID NO:73:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..9                                                            (D) OTHER INFORMATION: /label=SEQ73                                           /note= "Xaa denotes T or A at residue #2; T or S                              at residue #3; F or Y at residue #4; and A or S at                            residue #7"                                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:73:                                      TrpXaaXaaXaaLeuLysXaaArgLeu                                                   15                                                                            (2) INFORMATION FOR SEQ ID NO:74:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..9                                                            (D) OTHER INFORMATION: /label=SEQ74                                           /note= "Xaa denotes N or D"                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:74:                                      ProPheTyrPheXaaGluIleGlnSer                                                   15                                                                            (2) INFORMATION FOR SEQ ID NO:75:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ75                                           /note= "Xaa denotes F or Y at residue #7"                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:75:                                      GlySerAlaValCysXaaXaa                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:76:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ76                                           /note= "Xaa denotes P or A at residue #6"                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:76:                                      AsnSerAsnTrpLeuXaaVal                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:77:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ77                                           /note= "Xaa denotes E or D at residue #2; T, Q or S                           at residue #7"                                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:77:                                      ProXaaProArgProGlyXaaCys                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:78:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ78                                           /note= "Xaa denotes A or G"                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:78:                                      AspProTyrCysXaaTrpAsp                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:79:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ79                                           /note= "Xaa denotes N or G at residue #4; A or S at                           residue #5; Y, F, H or G at residue #6; and K, R, H, N or                     Q at residue #7"                                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:79:                                      CysGlyThrXaaXaaXaaXaa                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:80:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ80                                           /note= "Xaa denotes N or G at residue #4; A, S or N                           at residue #5; Y, F or H at residue #6; and K, R, H, N or                     Q at residue #7"                                                              (xi) SEQUENCE DESCRIPTION: SEQ ID NO:80:                                      CysGlyThrXaaXaaXaaXaa                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:81:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ81                                           /note= "Xaa denotes N or G at residue #4; and A or S                          at residue #5"                                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:81:                                      CysGlyThrXaaXaaXaaXaaPro                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:82:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ82                                           /note= "Xaa denotes K, F or Y at residue #2; F or Y                           at residue #4; F, Y, I or L at residue #5; F, Y or I at                       residue #6; and F or Y at residue #7"                                         (xi) SEQUENCE DESCRIPTION: SEQ ID NO:82:                                      AspXaaValXaaXaaXaaXaa                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:83:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ83                                           /note= "Xaa denotes V or I at residue #1; F or Y                              at residue #2; F, Y or L at residue #3; F, Y, I or L at                       residue #4; R or T at residue #6; and T or N at residue                       #8"                                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:83:                                      XaaXaaXaaXaaPheXaaXaaXaa                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:84:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ84                                           /note= "Xaa denotes V or I at residue #1; F or Y                              at residue #2; F, Y, I or L at residue #3; F, Y or I at                       residue #4; R or T at residue #6; and T or N at residue                       #8"                                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:84:                                      XaaXaaXaaXaaPheXaaXaaXaa                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:85:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ85                                           /note= "Xaa denotes V or I at residue #1; F or Y                              at residue #2; F, Y, I or L at residue #3; F, Y, I or L                       at residue #4; and T or N at residue #8"                                      (xi) SEQUENCE DESCRIPTION: SEQ ID NO:85:                                      XaaXaaXaaXaaPheArgXaaXaa                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:86:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ86                                           /note= "Xaa denotes V or I at residue #1; F or Y                              at residue #2; F, Y or L at residue #3; F, Y, I or L at                       residue #4; F or Y at residue #5, R or T at residue #6,                       E, D or V at residue #7; and T or N at residue #8"                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:86:                                      XaaXaaXaaXaaXaaXaaXaaXaa                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:87:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ87                                           /note= "Xaa denotes R, K or N at residue #1; T or A                           at residue #3; T, A or S at residue #4; F, Y or L at                          residue #5; and K or R at residue #7"                                         (xi) SEQUENCE DESCRIPTION: SEQ ID NO:87:                                      XaaTrpxaaXaaXaaLeuXaa                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:88:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..9                                                            (D) OTHER INFORMATION: /label=SEQ88                                           /note= "Xaa denotes T or A at residue #2; T, A or S                           at residue #3; F, Y or L at residue #4; A, S, V, I or L                       at residue #7"                                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:88:                                      TrpXaaXaaXaaLeuLysXaaXaaLeu                                                   15                                                                            (2) INFORMATION FOR SEQ ID NO:89:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..9                                                            (D) OTHER INFORMATION: /label=SEQ89                                           /note= "Xaa denotes T, A or S at residue #2; T, A or S                        at residue #3; F, Y or L at residue #4; A, S, I or L at                       residue #7"                                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:89:                                      TrpXaaXaaXaaLeuLysXaaXaaLeu                                                   15                                                                            (2) INFORMATION FOR SEQ ID NO:90:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..11                                                           (D) OTHER INFORMATION: /label=SEQ90                                           /note= "Xaa denotes T or A at residue #2; and T, A or S                       at residue #3"                                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:90:                                      TrpXaaXaaXaaLeuLysXaaXaaLeuXaaCys                                             1510                                                                          (2) INFORMATION FOR SEQ ID NO:91:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..9                                                            (D) OTHER INFORMATION: /label=SEQ91                                           /note= "Xaa denotes V, L or I at residue #1"                                  (xi) SEQUENCE DESCRIPTION: SEQ ID NO:91:                                      XaaProXaaProArgProGlyXaaCys                                                   15                                                                            (2) INFORMATION FOR SEQ ID NO:92:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ92                                           /note= "Xaa denotes K or Y at residue #2; F or Y                              at residue #4; F, Y or L at residue #5; F, Y, I or L at                       residue #6; and F or Y at residue #7"                                         (xi) SEQUENCE DESCRIPTION: SEQ ID NO:92:                                      AspXaaValXaaXaaXaaXaa                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:93:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..7                                                            (D) OTHER INFORMATION: /label=SEQ93                                           /note= "Xaa denotes K or Y at residue #2; F or Y                              at residue #4; F, Y, I or L at residue #5; F, Y or I at                       residue #6; and F or Y at residue #7"                                         (xi) SEQUENCE DESCRIPTION: SEQ ID NO:93:                                      AspXaaValXaaXaaXaaXaa                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:94:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ94                                           /note= "Xaa denotes V or I at residue #1; F, Y or L                           at residue #3; F, Y, I or L at residue #4; R or T at                          residue #6; and T or N at residue #8"                                         (xi) SEQUENCE DESCRIPTION: SEQ ID NO:94:                                      XaaTyrXaaXaaPheXaaXaaXaa                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:95:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ95                                           /note= "Xaa denotes V or I at residue #1; F, Y, I or L                        at residue #3; F, Y or I at residue #4; R or T at                             residue #6; and T or N at residue #8"                                         (xi) SEQUENCE DESCRIPTION: SEQ ID NO:95:                                      XaaTyrXaaXaaPheXaaXaaXaa                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:96:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ96                                           /note= "Xaa denotes V or I at residue #1; F, Y, I or L                        at residue #3; F, Y, I or L at residue #4; and T or N at                      residue #8"                                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:96:                                      XaaTyrXaaXaaPheArgXaaXaa                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:97:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ97                                           /note= "Xaa denotes F or Y at residue #2; F, Y or L                           at residue #3; F, Y, I or L at residue #4; F or Y at                          residue #5; R or T at residue #6; E, D, or V at residue                       #7; and T or N at residue #8"                                                 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:97:                                      ValXaaXaaXaaXaaXaaXaaXaa                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:98:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ98                                           /note= "Xaa denotes F or Y at residue #2; F, Y, I or L                        at residue #3; F, Y or I at residue #4; F or Y at                             residue #5; R or T at residue #6; E, D, or V at residue                       #7; and T or N at residue #8"                                                 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:98:                                      ValXaaXaaXaaXaaXaaXaaXaa                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:99:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ99                                           /note= "Xaa denotes F or Y at residue #2; F, Y, I or L                        at residue #3; F, Y, I or L at residue #4; F or Y at                          residue #5; E, D, or V at residue #7; and T or N at                           residue #8"                                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:99:                                      ValXaaXaaXaaXaaArgXaaXaa                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:100:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /label=SEQ100                                          /note= "Xaa denotes F or Y at residue #2; F, Y, I or L                        at residue #3; F, Y, I or L at residue #4; F or Y at                          residue #5; R or T at residue #6; E, D, or V at residue                       #7; and T or N at residue #8"                                                 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:100:                                     ValXaaXaaXaaXaaXaaXaaXaa                                                      15                                                                            __________________________________________________________________________

What is claimed is:
 1. A method of modulating a nerve, immune,virally-infected or transformed cell function, said method comprisingthe step of:contacting a nerve immunevirally-infected or transformedcell with an effective amount of a composition comprising an isolatedsemaphorin polypeptide comprising the amino acid sequence of SEQ IDNO:54, 56, 58, 60, 62 or 64, or a portion of said amino acid sequence,said portion sufficient to provide a semaphorin binding specificity andcomprising a peptide sequence selected from the group consisting of SEQID NOS:1-52 and 67-100, with the proviso that said polypeptide is otherthan a natural vaccinia or variola major virus open reading frametranslation product, whereby said polypeptide modulates a function ofsaid cell.
 2. A method according to claim 1, wherein said peptidesequence is selected from the group consisting of:(a) AspGlu!CysGlnLysArgAlaAsn!Asn TyrPheVal!Ile (SEQ ID NO:1)Cys GlnLysArgAlaAsn!AsnTyrPheVal!Ile ArgLysGlnThr! (SEQ ID NO:2) (b) CysGlyThr AsnGly!AlaSerAsn! TyrPheHisGly! LysArgHisAsnGln! (SEQ ID NO:3)CysGlyThr AsnGly!AlaSerAsn!XaaXaaPro (SEQ ID NO:4) CysGlyThr AsnGly!XaaXaaXaaProXaaCysAsp! (SEQ ID NO:5) CysGlyThrXaaXaaXaaXaaProXaa CysAsp!XaaXaa TyrIle!(SEQ ID NO:6) (c) ArgIleGlnVal! GlyAla! LeuValLys! CysSer!Pro PheTyr!AspAsn! (SEQ ID NO:7) CysSer!Pro PheTyr! AspAsn!Pro AspGluArgLys!HisLeuAsp! (SEQ ID NO:8) GlyXaa GlyAla!Xaa CysSer!ProTyr AspAsn!Pro (SEQID NO:9) (d) Leu PheTyr!Ser GlyAla!Thr ValAsnAla!Ala (SEQ ID NO:10)LeuPheTyr!SerXaaThrXaaAla AspGlu! PheTyr! (SEQ ID NO:11) PheTyr!SerGlyAla!Thr ValAsnAla!Ala AspGlu! PheTyr! (SEQ ID NO:12) (e) Leu AsnAsp!AlaLys!ProAsnPheVal (SEQ ID NO:13) (f) PhePhePheArgGlu (SEQ IDNO:14)PhePhe PheTyr!ArgGlu ThrAsn! (SEQ ID NO:15) PhePheArgGluThrAsn!Ala (SEQ ID NO:16) Phe PheTyr!ArgGlu ThrAsn!Ala (SEQ ID NO:17)TyrPhePhe PheTyr!ArgGlu (SEQ ID NO:18) PheTyr!PhePhe PheTyr!ArgGlu (SEQID NO:19) PheTyr! PheTyr! PheTyr!ArgGlu ThrAsn!Ala (SEQ ID NO:20)IleVal! PheTyr!Phe PheTyr! PheTyr!ArgGlu (SEQ ID NO:21) AspLysPheTyr!Val PheTyr! PheTyrIleLeu! PheTyrIleLeu! PheTyr! (SEQ ID NO:22)ValIle! PheTyr! PheTyrIleLeu! PheTyrIleLeu!Phe ArgThr!Xaa ThrAsn!(SEQ IDNO:23) ValIle! PheTyr! PheTyrIleLeu! PheTyrIleLeu! PheTyr! ArgThr!GluAspVal! ThrAsn! (SEQ ID NO:24) (g) Glu PheTyr!IleAsn CysSer!GlyLys(SEQ ID NO:25) PheTyr!IleAsnCysGlyLys AlaValIle! (SEQ ID NO:26) (h) ArgValIle! AlaGly! ArgGln! ValIle!CysLys (SEQ ID NO:27)Arg ValIle!XaaArgGln! ValIle!CysXaaXaaAsp (SEQ ID NO:28) GlyLys ValAlaIle!XaaXaaXaaArgValAlaIle!XaaXaaXaaCysLys (SEQ ID NO:29) (i) ArgLysAsn!Trp ThrAlaSer!ThrAlaSer! PheTyrLeu!Leu LysArg! (SEQ ID NO:30) PheTyr!Leu LysArg!AlaSer!ArgLeu AsnIle!Cys (SEQ ID NO:31) AsnIle!CysSer IleVal! ProSer!Gly(SEQ ID NO:32) Trp ThrAlaSer! ThrAlaSer! PheTyrLeu!LeuLysAlaSerValIleLeu!XaaLeu (SEQ ID NO:33) Trp ThrAlaSer!ThrAlaSer!XaaLeuLysXaaXaaLeuXaaCys (SEQ ID NO:34) TrpXaaThrSer!XaaLeuLysXaaXaaLeuXaaCys (SEQ ID NO:35) (j) PheTyr! PheTyr!AsnAsp!GluIleGlnSer (SEQ ID NO:36) PheTyr!Pro PheTyr! PheTyr! PheTyr!AsnAsp!Glu (SEQ ID NO:37) (k) GlySerAla ValIleLeu!CysXaa PheTyr! (SEQ IDNO:38)SerAla ValIleLeu!CysXaa PheTyr!XaaMet (SEQ ID NO:39) (l) AsnSerAsnAla!TrpLeu ProAla!Val (SEQ ID NO:40) (m) ValLeuIle!ProGluAspTyrSerPhe!ProArgProGly (SEQ ID NO:41) ValLeuIle!ProXaaProArgAla!ProGlyXaaCys (SEQ ID NO:42) Pro GluAspTyrSerPhe!ProArgProGlyThrGlnSer!Cys (SEQ ID NO:43) (n) AspPro HisPheTyr!Cys AlaGly!Trp (SEQ IDNO:44)Pro HisPheTyr!Cys AlaGly!TrpAsp (SEQ ID NO:45) AspProXaaCysAlaGly!TrpAsp (SEQ ID NO:46) CysXaaXaaXaaXaaAspProXaaCysXaaTrpAsp (SEQID NO:47) CysXaaXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:48)CysXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:49)CysXaaXaaCysXaaXaaXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:50)CysXaaXaaCysXaaXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO: 51), andCysXaaXaaCysXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:52).
 3. A methodaccording to claim 1, wherein said peptide sequence is selected from thegroup consisting of:(a) AspCysGlnAsnTyrIle (SEQ ID NO:67) (b) CysGlyThrAsnGly! AlaSer!XaaXaaPro (SEQ ID NO:68) (c) GlyXaa SerCys!ProTyrAspPro(SEQ ID NO:69) (d) LeuTyrSerGlyThr ValAsnAla!Ala (SEQ ID NO:70) (e)LeuAsnAlaProAsnPheVal (SEQ ID NO:71) (f) PheTyr!PhePhe PheTyr!ArgGlu(SEQ ID NO:19) (g) Glu PheTyr!IleAsn CysSer!GlyLys (SEQ ID NO:25) (h)Arg ValIle!AlaArgValCysLys (SEQ ID NO:72) (i) Trp ThrAla! ThrSer!PheTyr!LeuLys AlaSer!ArgLeu (SEQ ID NO:73) (j) ProPheTyrPheAsnAsp!GluIleGlnSer (SEQ ID NO:74) (k) GlySerAlaValCysXaa PheTyr! (SEQID NO:75) (l) AsnSerAsnTrpLeu ProAla!Val (SEQ ID NO:76) (m) ProGluAsp!ProArgProGly ThrGlnSer!Cys (SEQ ID NO:77), and (n) AspProTyrCysAlaGly!TrpAsp (SEQ ID NO:78).
 4. A method according to claim 1, whereinsaid peptide sequence is selected from the group consisting of:(a)AspGlu!Cys GlnLysArgAlaAsn!Asn TyrPheVal!Ile (SEQ ID NO:01)CysGlnLysArgAlaAsn!Asn TyrPheVal!Ile ArgLysGlnThr! (SEQ ID NO:02) (b)CysGlyThr AsnGly! AlaSer! TyrPheHisGly! LysArgHisAsnGln! (SEQ IDNO:79)CysGlyThr AsnGly! AlaSerAsn! TyrPheHis! LysArgHisAsnGln! (SEQ IDNO:80) CysGlyThr AsnGly! AlaSer!XaaXaaPro (SEQ ID NO:81) (c)ArgIleGlnVal! GlyAla! LeuValLys! CysSer!Pro PheTyr! AspAsn! (SEQ IDNO:07) CysSer!Pro PheTyr! AspAsn!Pro AspGluArgLys! HisLeuAsp! (SEQ IDNO:08) GlyXaa GlyAla!Xaa CysSer!ProTyr AspAsn!Pro (SEQ ID NO:09) (d) LeuPheTyr!Ser GlyAla!Thr ValAsnAla!Ala (SEQ ID NO:10)LeuPheTyr!SerXaaThrXaaAla AspGlu! PheTyr! (SEQ ID NO:11) PheTyr!SerGlyAla!Thr ValAsnAla!Ala AspGlu! PheTyr! (SEQ ID NO:12) (e) Leu AsnAsp!AlaLys!ProAsnPheVal (SEQ ID NO:13) (f) PhePhePheArgGlu (SEQ IDNO:14)PhePhe PheTyr!ArgGlu ThrAsn! (SEQ ID NO:15) PhePheArgGluThrAsn!Ala (SEQ ID NO:16) Phe PheTyr!ArgGlu ThrAsn!Ala (SEQ ID NO:17)TyrPhePhe PheTyr!ArgGlu (SEQ ID NO:18) PheTyr!PhePhe PheTyr!ArgGlu (SEQID NO:19) PheTyr! PheTyr! PheTyr!ArgGlu ThrAsn!Ala (SEQ ID NO:20)IleVal! PheTyr!Phe PheTyr! PheTyr!ArgGlu (SEQ ID NO:21) AspLysPheTyr!Val PheTyr! PheTyrLeu! PheTyrIleLeu! PheTyr! (SEQ ID NO:22)Asp LysPheTyr!Val PheTyr! PheTyrIleLeu! PheTyrIle! PheTyr! (SEQ IDNO:82) ValIle! PheTyr! PheTyrLeu! PheTyrIleLeu!Phe ArgThr!Xaa ThrAsn!(SEQ ID NO:83) ValIle! PheTyr! PheTyrIleLeu! PheTyrIle!Phe ArgThr!XaaThrAsn! (SEQ ID NO:84) ValIle! PheTyr! PheTyrIleLeu!PheTyrIleLeu!PheArgXaa ThrAsn! (SEQ ID NO:85) ValIle! PheTyr! PheTyrLeu!PheTyrIleLeu! PheTyr! ArgThr! GluAspVal! ThrAsn! (SEQ ID NO:86) (g) GluPheTyr!IleAsn CysSer!GlyLys (SEQ ID NO:25) PheTyr!IleAsnCysGlyLysAlaValIle! (SEQ ID NO:26) (h) Arg ValIle! AlaGly! ArgGln! ValIle!CysLys(SEQ ID NO:27)Arg ValIle!Xaa ArgGln! ValIle!CysXaaXaaAsp (SEQ ID NO:28)GlyLys ValAlaIle!XaaXaaXaaArg ValAlaIle!XaaXaaXaaCysLys (SEQ ID NO:29)(i) ArgLysAsn!Trp ThrAla! ThrAlaSer! PheTyrLeu!Leu LysArg! (SEQ IDNO:87) PheTyr!Leu LysArg! AlaSer!ArgLeu AsnIle!Cys (SEQ ID NO:31)AsnIle!CysSer IleVal! ProSer!Gly (SEQ ID NO:32) Trp ThrAla! ThrAlaSer!PheTyrLeu!LeuLys AlaSerValIleLeu!XaaLeu (SEQ ID NO:88) Trp ThrAlaSer!ThrAlaSer! PheTyrLeu!LeuLys AlaSerIleLeu!XaaLeu (SEQ ID NO:89) TrpThrAla! ThrAlaSer!XaaLeuLysXaaXaaLeuXaaCys (SEQ ID NO:90) (j) PheTyr!PheTyr! AsnAsp!GluIleGlnSer (SEQ ID NO:36) PheTyr!Pro PheTyr! PheTyr!PheTyr! AsnAsp!Glu (SEQ ID NO:37) (k) GlySerAla ValIleLeu!CysXaa PheTyr!(SEQ ID NO:38)SerAla ValIle!CysXaa PheTyr!XaaMet (SEQ ID NO:39) (l)AsnSer AsnAla!TrpLeu ProAla!Val (SEQ ID NO:40) (m) ValLeuIle!ProGluAspTyrSerPhe!ProArgProGly (SEQ ID NO:41)ValLeuIle!ProXaaProArgProGlyXaaCys (SEQ ID NO:91) ProGluAspTyrSerPhe!ProArgProGly ThrGlnSer!Cys (SEQ ID NO:43) (n) AspProHisPheTyr!Cys AlaGly!Trp (SEQ ID NO:44)Pro HisPheTyr!Cys AlaGly!TrpAsp(SEQ ID NO:45) AspProXaaCys AlaGly!TrpAsp (SEQ ID NO:46)CysXaaXaaXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:47)CysXaaXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:48)CysXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:49)CysXaaXaaCysXaaXaaXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:50)CysXaaXaaCysXaaXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:51), andCysXaaXaaCysXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:52).
 5. A methodaccording to claim 1, wherein said peptide sequence is selected from thegroup consisting of:(f) TyrPhePhe PheTyr!ArgGlu (SEQ ID NO:18)AspLysTyr!Val PheTyr! PheTyrLeu! PheTyrIleLeu! PheTyr! (SEQ ID NO:92) AspLysTyr!Val PheTyr! PheTyrIleLeu! PheTyrIle! PheTyr! (SEQ ID NO:93)ValIle!Tyr PheTyrLeu! PheTyrIleLeu!Phe ArgThr!Xaa ThrAsn! (SEQ ID NO:94)ValIle!Tyr PheTyrIleLeu! PheTyrIle!Phe ArgThr!Xaa ThrAsn! (SEQ ID NO:95)ValIle!Tyr PheTyrIleLeu! PheTyrIleLeu!PheArgXaa ThrAsn! (SEQ ID NO:96)Val PheTyr! PheTyrLeu! PheTyrIleLeu! PheTyr! ArgThr! GluAspVal! ThrAsn!(SEQ ID NO:97) Val PheTyr! PheTyrIleLeu! PheTyrIle! PheTyr! ArgThr!GluAspVal! ThrAsn! (SEQ ID NO:98) Val PheTyr! PheTyrIleLeu!PheTyrIleLeu! PheTyr!Arg GluAspVal! ThrAsn! (SEQ ID NO:99) (n)CysXaaXaaXaaAspProXaaCysXaaTrpAsp (SEQ IDNO:48)CysXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:49)CysXaaXaaCysXaaXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:51), andCysXaaXaaCysXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:52).
 6. A methodaccording to claim 1, wherein said peptide sequence is selected from thegroup consisting of:(b) CysGlyThr AsnGly! AlaSerAsn! TyrPheHisGly!LysArgHisAsnGln! (SEQ ID NO:03)CysGlyThr AsnGly! AlaSerAsn!XaaXaaPro(SEQ ID NO:04) CysGlyThr AsnGly!XaaXaaXaaProXaa CysAsp! (SEQ ID NO:05)CysGlyThrXaaXaaXaaXaaProXaa CysAsp!XaaXaa TyrIle! (SEQ ID NO:06) (f) AspLysPheTyr!Val PheTyr! PheTyrIleLeu! PheTyrIleLeu! PheTyr! (SEQ ID NO:22)ValIle! PheTyr! PheTyrIleLeu! PheTyrIleLeu!Phe ArgThr!Xaa ThrAsn! (SEQID NO:23) Val PheTyr! PheTyrIleLeu! PheTyrIleLeu! PheTyr! ArgThr!GluAspVal! ThrAsn! (SEQ ID NO:100) (i) ArgLysAsn!Trp ThrAlaSer!ThrAlaSer! PheTyrLeu!Leu LysArg! (SEQ ID NO:30)Trp ThrAlaSer! ThrAlaSer!PheTyrLeu!LeuLys AlaSerValIleLeu!XaaLeu (SEQ ID NO:33) Trp ThrAlaSer!ThrAlaSer!XaaLeuLysXaaXaaLeuXaaCys (SEQ ID NO:34) TrpXaaThrSer!XaaLeuLysXaaXaaLeuXaaCys (SEQ ID NO:35) (k) SerAlaValIleLeu!CysXaa PheTyr!XaaMet (SEQ ID NO:39), and (m)ValLeuIle!ProXaaPro ArgAla!ProGlyXaaCys (SEQ ID NO:42).
 7. A method ofmodulating a nerve, immune, virally-infected or transformed cellfunction, said method comprising the step of:contacting a nerve immune,virally-infected or transformed cell with an effective amount of acomposition comprising an isolated polypeptide comprising the amino acidsequence of SEQ ID NO:54, 58, 60, 62, or 64; or a portion of said aminoacid sequence, said portion sufficient to provide a semaphorin bindingspecificity and comprising a peptide sequence selected from the groupconsisting of SEQ ID NOS:1-52 and 67-100, and with the proviso that saidpeptide sequence is contained within neither SEQ ID NO:56 nor 66,whereby said polypeptide modulates a function of said cell.
 8. A methodaccording to claim 7, wherein said peptide sequence is selected from thegroup consisting of:(a) AspGlu!Cys GlnLysArgAlaAsn!Asn TyrPheVal!Ile(SEQ ID NO:1)Cys GlnLysArgAlaAsn!Asn TyrPheVal!Ile ArgLysGlnThr! (SEQ IDNO:2) (b) CysGlyThr AsnGly! AlaSerAsn! TyrPheHisGly! LysArgHisAsnGln!(SEQ ID NO:3)CysGlyThr AsnGly! AlaSerAsn!XaaXaaPro (SEQ ID NO:4)CysGlyThr AsnGly!XaaXaaXaaProXaa CysAsp! (SEQ ID NO:5)CysGlyThrXaaXaaXaaXaaProXaa CysAsp!XaaXaa TyrIle! (SEQ ID NO:6) (c)ArgIleGlnVal! GlyAla! LeuValLys! CysSer!Pro PheTyr! AspAsn! (SEQ IDNO:7) CysSer!Pro PheTyr! AspAsn!Pro AspGluArgLys! HisLeuAsp! (SEQ IDNO:8) GlyXaa GlyAla!Xaa CysSer!ProTyr AspAsn!Pro (SEQ ID NO:9) (d) LeuPheTyr!Ser GlyAla!Thr ValAsnAla!Ala (SEQ ID NO:10)LeuPheTyr!SerXaaThrXaaAla AspGlu! PheTyr! (SEQ ID NO:11) PheTyr!SerGlyAla!Thr ValAsnAla!Ala AspGlu! PheTyr! (SEQ ID NO:12) (e) Leu AsnAsp!AlaLys!ProAsnPheVal (SEQ ID NO:13) (f) PhePhePheArgGlu (SEQ IDNO:14)PhePhe PheTyr!ArgGlu ThrAsn! (SEQ ID NO:15) PhePheArgGluThrAsn!Ala (SEQ ID NO:16) Phe PheTyr!ArgGlu ThrAsn!Ala (SEQ ID NO:17)TyrPhePhe PheTyr!ArgGlu (SEQ ID NO:18) PheTyr!PhePhe PheTyr!ArgGlu (SEQID NO:19) PheTyr! PheTyr! PheTyr!ArgGlu ThrAsn!Ala (SEQ ID NO:20)IleVal! PheTyr!Phe PheTyr! PheTyr!ArgGlu (SEQ ID NO:21) AspLysPheTyr!Val PheTyr! PheTyrIleLeu! PheTyrIleLeu! PheTyr! (SEQ ID NO:22)ValIle! PheTyr! PheTyrIleLeu! PheTyrIleLeu!Phe ArgThr!Xaa ThrAsn!(SEQ IDNO:23) ValIle! PheTyr! PheTyrIleLeu! PheTyrIleLeu! PheTyr! ArgThr!GluAspVal! ThrAsn! (SEQ ID NO:24) (g) Glu PheTyr!IleAsn CysSer!GlyLys(SEQ ID NO:25) PheTyr!IleAsnCysGlyLys AlaValIle! (SEQ ID NO:26) (h) ArgValIle! AlaGly! ArgGln! ValIle!CysLys (SEQ ID NO:27)Arg ValIle!XaaArgGln! ValIle!CysXaaXaaAsp (SEQ ID NO:28) GlyLys ValAlaIle!XaaXaaXaaArgValAlaIle!XaaXaaXaaCysLys (SEQ ID NO:29) (i) ArgLysAsn!Trp ThrAlaSer!ThrAlaSer! PheTyrLeu!Leu LysArg! (SEQ ID NO:30) PheTyr!Leu LysArg!AlaSer!ArgLeu AsnIle!Cys (SEQ ID NO:31) AsnIle!CysSer IleVal! ProSer!Gly(SEQ ID NO:32) Trp ThrAlaSer! ThrAlaSer! PheTyrLeu!LeuLysAlaSerValIleLeu!XaaLeu (SEQ ID NO:33) Trp ThrAlaSer!ThrAlaSer!XaaLeuLysXaaXaaLeuXaaCys (SEQ ID NO:34) TrpXaaThrSer!XaaLeuLysXaaXaaLeuXaaCys (SEQ ID NO:35) (j) PheTyr! PheTyr!AsnAsp!GluIleGlnSer (SEQ ID NO:36) PheTyr!Pro PheTyr! PheTyr! PheTyr!AsnAsp!Glu (SEQ ID NO:37) (k) GlySerAla ValIleLeu!CysXaa PheTyr! (SEQ IDNO:38)SerAla ValIleLeu!CysXaa PheTyr!XaaMet (SEQ ID NO:39) (l) AsnSerAsnAla!TrpLeu ProAla!Val (SEQ ID NO:40) (m) ValLeuIle!ProGluAspTyrSerPhe!ProArgProGly (SEQ ID NO:41) ValLeuIle!ProXaaProArgAla!ProGlyXaaCys (SEQ ID NO:42) Pro GluAspTyrSerPhe!ProArgProGlyThrGlnSer!Cys (SEQ ID NO:43) (n) AspPro HisPheTyr!Cys AlaGly!Trp (SEQ IDNO:44)Pro HisPheTyr!Cys AlaGly!TrpAsp (SEQ ID NO:45) AspProXaaCysAlaGly!TrpAsp (SEQ ID NO:46) CysXaaXaaXaaXaaAspProXaaCysXaaTrpAsp (SEQID NO:47) CysXaaXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:48)CysXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:49)CysXaaXaaCysXaaXaaXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:50)CysXaaXaaCysXaaXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:51), andCysXaaXaaCysXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:52).
 9. A methodaccording to claim 7, wherein said peptide sequence is selected from thegroup consisting of:(a) AspCysGlnAsnTyrIle (SEQ ID NO:67) (b) CysGlyThrAsnGly! AlaSer!XaaXaaPro (SEQ ID NO:68) (c) GlyXaa SerCys!ProTyrAspPro(SEQ ID NO:69) (d) LeuTyrSerGlyThr ValAsnAla!Ala (SEQ ID NO:70) (e)LeuAsnAlaProAsnPheVal (SEQ ID NO:71) (f) PheTyr!PhePhe PheTyr!ArgGlu(SEQ ID NO:19) (g) Glu PheTyr!IleAsn CysSer!GlyLys (SEQ ID NO:25) (h)Arg ValIle!AlaArgValCysLys (SEQ ID NO:72) (i) Trp ThrAla! ThrSer!PheTyr!LeuLys AlaSer!ArgLeu (SEQ ID NO:73) (j) ProPheTyrPheAsnAsp!GluIleGlnSer (SEQ ID NO:74) (k) GlySerAlaValCysXaa PheTyr! (SEQID NO:75) (l) AsnSerAsnTrpLeu ProAla!Val (SEQ ID NO:76) (m) ProGluAsp!ProArgProGly ThrGlnSer!Cys (SEQ ID NO:77), and (n) AspProTyrCysAlaGly!TrpAsp (SEQ ID NO:78).
 10. A method according to claim 7, whereinsaid peptide sequence is selected from the group consisting of:(a)AspGlu!Cys GlnLysArgAlaAsn!Asn TyrPheVal!Ile (SEQ ID NO:01)CysGlnLysArgAlaAsn!Asn TyrPheVal!Ile ArgLysGlnThr! (SEQ ID NO:02) (b)CysGlyThr AsnGly! AlaSer! TyrPheHisGly! LysArgHisAsnGln! (SEQ IDNO:79)CysGlyThr AsnGly! AlaSerAsn! TyrPheHis! LysArgHisAsnGln! (SEQ IDNO:80) CysGlyThr AsnGly! AlaSer!XaaXaaPro (SEQ ID NO:81) (c)ArgIleGlnVal! GlyAla! LeuValLys! CysSer!Pro PheTyr! AspAsn! (SEQ IDNO:07) CysSer!Pro PheTyr! AspAsn!Pro AspGluArgLys! HisLeuAsp! (SEQ IDNO:08) GlyXaa GlyAla!Xaa CysSer!ProTyr AspAsn!Pro (SEQ ID NO:09) (d) LeuPheTyr!Ser GlyAla!Thr ValAsnAla!Ala (SEQ ID NO:10)LeuPheTyr!SerXaaThrXaaAla AspGlu! PheTyr! (SEQ ID NO:11) PheTyr!SerGlyAla!Thr ValAsnAla!Ala AspGlu! PheTyr! (SEQ ID NO:12) (e) Leu AsnAsp!AlaLys!ProAsnPheVal (SEQ ID NO:13) (f) PhePhePheArgGlu (SEQ IDNO:14)PhePhe PheTyr!ArgGlu ThrAsn! (SEQ ID NO:15) PhePheArgGluThrAsn!Ala (SEQ ID NO:16) Phe PheTyr!ArgGlu ThrAsn!Ala (SEQ ID NO:17)TyrPhePhe PheTyr!ArgGlu (SEQ ID NO:18) PheTyr!PhePhe PheTyr!ArgGlu (SEQID NO:19) PheTyr! PheTyr! PheTyr!ArgGlu ThrAsn!Ala (SEQ ID NO:20)IleVal! PheTyr!Phe PheTyr! PheTyr!ArgGlu (SEQ ID NO:21) AspLysPheTyr!Val PheTyr! PheTyrLeu! PheTyrIleLeu! PheTyr! (SEQ ID NO:22)Asp LysPheTyr!Val PheTyr! PheTyrIleLeu! PheTyrIle! PheTyr! (SEQ IDNO:82) ValIle! PheTyr! PheTyrLeu! PheTyrIleLeu!Phe ArgThr!Xaa ThrAsn!(SEQ ID NO:83) ValIle! PheTyr! PheTyrIleLeu! PheTyrIle!Phe ArgThr!XaaThrAsn! (SEQ ID NO:84) ValIle! PheTyr! PheTyrIleLeu!PheTyrIleLeu!PheArgXaa ThrAsn! (SEQ ID NO:85) ValIle! PheTyr! PheTyrLeu!PheTyrIleLeu! PheTyr! ArgThr! GluAspVal! ThrAsn! (SEQ ID NO:86) (g) GluPheTyr!IleAsn CysSer!GlyLys (SEQ ID NO:25) PheTyr!IleAsnCysGlyLysAlaValIle! (SEQ ID NO:26) (h) Arg ValIle! AlaGly! ArgGln! ValIle!CysLys(SEQ ID NO:27)Arg ValIle!Xaa ArgGln! ValIle!CysXaaXaaAsp (SEQ ID NO:28)GlyLys ValAlaIle!XaaXaaXaaArg ValAlaIle!XaaXaaXaaCysLys (SEQ ID NO:29)(i) ArgLysAsn!Trp ThrAla! ThrAlaSer! PheTyrLeu!Leu LysArg! (SEQ IDNO:87) PheTyr!Leu LysArg! AlaSer!ArgLeu AsnIle!Cys (SEQ ID NO:31)AsnIle!CysSer IleVal! ProSer!Gly (SEQ ID NO:32) Trp ThrAla! ThrAlaSer!PheTyrLeu!LeuLys AlaSerValIleLeu!XaaLeu (SEQ ID NO:88) Trp ThrAlaSer!ThrAlaSer! PheTyrLeu!LeuLys AlaSerIleLeu!XaaLeu (SEQ ID NO:89) TrpThrAla! ThrAlaSer!XaaLeuLysXaaXaaLeuXaaCys (SEQ ID NO:90) (j) PheTyr!PheTyr! AsnAsp!GluIleGlnSer (SEQ ID NO:36) PheTyr!Pro PheTyr! PheTyr!PheTyr! AsnAsp!Glu (SEQ ID NO:37) (k) GlySerAla ValIleLeu!CysXaa PheTyr!(SEQ ID NO:38) SerAla ValIle!CysXaa PheTyr!XaaMet (SEQ ID NO:39) (l)AsnSer AsnAla!TrpLeu ProAla!Val (SEQ ID NO:40) (m) ValLeuIle!ProGluAspTyrSerPhe!ProArgProGly (SEQ ID NO:41)ValLeuIle!ProXaaProArgProGlyXaaCys (SEQ ID NO:91) ProGluAspTyrSerPhe!ProArgProGly ThrGlnSer!Cys (SEQ ID NO:43) (n) AspProHisPheTyr!Cys AlaGly!Trp (SEQ ID NO:44)Pro HisPheTyr!Cys AlaGly!TrpAsp(SEQ ID NO:45) AspProXaaCys AlaGly!TrpAsp (SEQ ID NO:46)CysXaaXaaXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:47)CysXaaXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:48)CysXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:49)CysXaaXaaCysXaaXaaXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:50)CysXaaXaaCysXaaXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:51), andCysXaaXaaCysXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:52).
 11. A methodaccording to claim 7, wherein said peptide sequence is selected from thegroup consisting of:(f) TyrPhePhe PheTyr!ArgGlu (SEQ ID NO:18)AspLysTyr!Val PheTyr! PheTyrLeu! PheTyrIleLeu! PheTyr! (SEQ ID NO:92) AspLysTyr!Val PheTyr! PheTyrIleLeu! PheTyrIle! PheTyr! (SEQ ID NO:93)ValIle!Tyr PheTyrLeu! PheTyrIleLeu!Phe ArgThr!Xaa ThrAsn! (SEQ ID NO:94)ValIle!Tyr PheTyrIleLeu! PheTyrIle!Phe ArgThr!Xaa ThrAsn! (SEQ ID NO:95)ValIle!Tyr PheTyrIleLeu! PheTyrIleLeu!PheArgXaa ThrAsn! (SEQ ID NO:96)Val PheTyr! PheTyrLeu! PheTyrIleLeu! PheTyr! ArgThr! GluAspVal! ThrAsn!(SEQ ID NO:97) Val PheTyr! PheTyrIleLeu! PheTyrIle! PheTyr! ArgThr!GluAspVal! ThrAsn! (SEQ ID NO:98) Val PheTyr! PheTyrIleLeu!PheTyrIleLeu! PheTyr!Arg GluAspVal! ThrAsn! (SEQ ID NO:99) (n)CysXaaXaaXaaAspProXaaCysXaaTrpAsp (SEQ IDNO:48)CysXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:49)CysXaaXaaCysXaaXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:51), andCysXaaXaaCysXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:52).
 12. A method ofmodulating a nerve, immune, virally-infected or transformed cellfunction, said method comprising the step of:contacting a nerve, immune,virally-infected or transformed cell with an effective amount of acomposition comprising an isolated semaphorin polypeptide comprising theamino acid sequence of SEQ ID NO:54, 58, 60, 62, or 64; or a portion ofsaid amino acid sequence, said portion sufficient to provide asemaphorin binding specificity and comprising a peptide sequenceselected from the group consisting of SEQ ID NOS:1-52 and 67-100, andwith the proviso that said peptide sequence is other than a sequenceoccurring in a natural vaccinia or variola major virus open readingframe translation product, whereby said polypeptide modulates a functionof said cell.
 13. A method according to claim 12, wherein said peptidesequence is selected from the group consisting of:(a) AspGlu!CysGlnLysArgAlaAsn!Asn TyrPheVal!Ile (SEQ ID NO:1)Cys GlnLysArgAlaAsn!AsnTyrPheVal!Ile ArgLysGlnThr! (SEQ ID NO:2) (b) CysGlyThr AsnGly!AlaSerAsn! TyrPheHisGly! LysArgHisAsnGln! (SEQ ID NO:3)CysGlyThr AsnGly!AlaSerAsn!XaaXaaPro (SEQ ID NO:4) CysGlyThr AsnGly!XaaXaaXaaProXaaCysAsp! (SEQ ID NO:5) CysGlyThrXaaXaaXaaXaaProXaa CysAsp!XaaXaa TyrIle!(SEQ ID NO:6) (c) ArgIleGlnVal! GlyAla! LeuValLys! CysSer!Pro PheTyr!AspAsn! (SEQ ID NO:7) CysSer!Pro PheTyr! AspAsn!Pro AspGluArgLys!HisLeuAsp! (SEQ ID NO:8) GlyXaa GlyAla!Xaa CysSer!ProTyr AspAsn!Pro (SEQID NO:9) (d) Leu PheTyr!Ser GlyAla!Thr ValAsnAla!Ala (SEQ ID NO:10)LeuPheTyr!SerXaaThrXaaAla AspGlu! PheTyr! (SEQ ID NO:11) PheTyr!SerGlyAla!Thr ValAsnAla!Ala AspGlu! PheTyr! (SEQ ID NO:12) (e) Leu AsnAsp!AlaLys!ProAsnPheVal (SEQ ID NO:13) (f) PhePhePheArgGlu (SEQ IDNO:14)PhePhe PheTyr!ArgGlu ThrAsn! (SEQ ID NO:15) PhePheArgGluThrAsn!Ala (SEQ ID NO:16) Phe PheTyr!ArgGlu ThrAsn!Ala (SEQ ID NO:17)TyrPhePhe PheTyr!ArgGlu (SEQ ID NO:18) PheTyr!PhePhe PheTyr!ArgGlu (SEQID NO:19) PheTyr! PheTyr! PheTyr!ArgGlu ThrAsn!Ala (SEQ ID NO:20)IleVal! PheTyr!Phe PheTyr! PheTyr!ArgGlu (SEQ ID NO:21) AspLysPheTyr!Val PheTyr! PheTyrIleLeu! PheTyrIleLeu! PheTyr! (SEQ ID NO:22)ValIle! PheTyr! PheTyrIleLeu! PheTyrIleLeu!Phe ArgThr!Xaa ThrAsn!(SEQ IDNO:23) ValIle! PheTyr! PheTyrIleLeu! PheTyrIleLeu! PheTyr! ArgThr!GluAspVal! ThrAsn! (SEQ ID NO:24) (g) Glu PheTyr!IleAsn CysSer!GlyLys(SEQ ID NO:25) PheTyr!IleAsnCysGlyLys AlaValIle! (SEQ ID NO:26) (h) ArgValIle! AlaGly! ArgGln! ValIle!CysLys (SEQ ID NO:27)Arg ValIle!XaaArgGln! ValIle!CysXaaXaaAsp (SEQ ID NO:28) GlyLys ValAlaIle!XaaXaaXaaArgValAlaIle!XaaXaaXaaCysLys (SEQ ID NO:29) (i) ArgLysAsn!Trp ThrAlaSer!ThrAlaSer! PheTyrLeu!Leu LysArg! (SEQ ID NO:30) PheTyr!Leu LysArg!AlaSer!ArgLeu AsnIle!Cys (SEQ ID NO:31) AsnIle!CysSer IleVal! ProSer!Gly(SEQ ID NO:32) Trp ThrAlaSer! ThrAlaSer! PheTyrLeu!LeuLysAlaSerValIleLeu!XaaLeu (SEQ ID NO:33) Trp ThrAlaSer!ThrAlaSer!XaaLeuLysXaaXaaLeuXaaCys (SEQ ID NO:34) TrpXaaThrSer!XaaLeuLysXaaXaaLeuXaaCys (SEQ ID NO:35) (j) PheTyr! PheTyr!AsnAsp!GluIleGlnSer (SEQ ID NO:36) PheTyr!Pro PheTyr! PheTyr! PheTyr!AsnAsp!Glu (SEQ ID NO:37) (k) GlySerAla ValIleLeu!CysXaa PheTyr! (SEQ IDNO:38)SerAla ValIleLeu!CysXaa PheTyr!XaaMet (SEQ ID NO:39) (l) AsnSerAsnAla!TrpLeu ProAla!Val (SEQ ID NO:40) (m) ValLeuIle!ProGluAspTyrSerPhe!ProArgProGly (SEQ ID NO:41) ValLeuIle!ProXaaProArgAla!ProGlyXaaCys (SEQ ID NO:42) Pro GluAspTyrSerPhe!ProArgProGlyThrGlnSer!Cys (SEQ ID NO:43) (n) AspPro HisPheTyr!Cys AlaGly!Trp (SEQ IDNO:44)Pro HisPheTyr!Cys AlaGly!TrpAsp (SEQ ID NO:45) AspProXaaCysAlaGly!TrpAsp (SEQ ID NO:46) CysXaaXaaXaaXaaAspProXaaCysXaaTrpAsp (SEQID NO:47) CysXaaXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:48)CysXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:49)CysXaaXaaCysXaaXaaXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:50)CysXaaXaaCysXaaXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:51), andCysXaaXaaCysXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:52).
 14. A methodaccording to claim 12, wherein said peptide sequence is selected fromthe group consisting of:(a) AspCysGlnAsnTyrIle (SEQ ID NO:67) (b)CysGlyThr AsnGly! AlaSer!XaaXaaPro (SEQ ID NO:68) (c) GlyXaaSerCys!ProTyrAspPro (SEQ ID NO:69) (d) LeuTyrSerGlyThr ValAsnAla!Ala(SEQ ID NO:70) (e) LeuAsnAlaProAsnPheVal (SEQ ID NO:71) (f)PheTyr!PhePhe PheTyr!ArgGlu (SEQ ID NO:19) (g) Glu PheTyr!IleAsnCysSer!GlyLys (SEQ ID NO:25) (h) Arg ValIle!AlaArgValCysLys (SEQ IDNO:72) (i) Trp ThrAla! ThrSer! PheTyr!LeuLys AlaSer!ArgLeu (SEQ IDNO:73) (j) ProPheTyrPhe AsnAsp!GluIleGlnSer (SEQ ID NO:74) (k)GlySerAlaValCysXaa PheTyr! (SEQ ID NO:75) (l) AsnSerAsnTrpLeu ProAla!Val(SEQ ID NO:76) (m) Pro GluAsp!ProArgProGly ThrGlnSer!Cys (SEQ ID NO:77),and (n) AspProTyrCys AlaGly!TrpAsp (SEQ ID NO:78).
 15. A methodaccording to claim 12, wherein said peptide sequence is selected fromthe group consisting of:(a) AspGlu!Cys GlnLysArgAlaAsn!Asn TyrPheVal!Ile(SEQ ID NO:01)Cys GlnLysArgAlaAsn!Asn TyrPheVal!Ile ArgLysGlnThr! (SEQID NO:02) (b) CysGlyThr AsnGly! AlaSer! TyrPheHisGly! LysArgHisAsnGln!(SEQ ID NO:79)CysGlyThr AsnGly! AlaSerAsn! TyrPheHis! LysArgHisAsnGln!(SEQ ID NO:80) CysGlyThr AsnGly! AlaSer!XaaXaaPro (SEQ ID NO:81) (c)ArgIleGlnVal! GlyAla! LeuValLys! CysSer!Pro PheTyr! AspAsn! (SEQ IDNO:07) CysSer!Pro PheTyr! AspAsn!Pro AspGluArgLys! HisLeuAsp! (SEQ IDNO:08) GlyXaa GlyAla!Xaa CysSer!ProTyr AspAsn!Pro (SEQ ID NO:09) (d) LeuPheTyr!Ser GlyAla!Thr ValAsnAla!Ala (SEQ ID NO:10)LeuPheTyr!SerXaaThrXaaAla AspGlu! PheTyr! (SEQ ID NO:11) PheTyr!SerGlyAla!Thr ValAsnAla!Ala AspGlu! PheTyr! (SEQ ID NO:12) (e) Leu AsnAsp!AlaLys!ProAsnPheVal (SEQ ID NO:13) (f) PhePhePheArgGlu (SEQ IDNO:14)PhePhe PheTyr!ArgGlu ThrAsn! (SEQ ID NO:15) PhePheArgGluThrAsn!Ala (SEQ ID NO:16) Phe PheTyr!ArgGlu ThrAsn!Ala (SEQ ID NO:17)TyrPhePhe PheTyr!ArgGlu (SEQ ID NO:18) PheTyr!PhePhe PheTyr!ArgGlu (SEQID NO:19) PheTyr! PheTyr! PheTyr!ArgGlu ThrAsn!Ala (SEQ ID NO:20)IleVal! PheTyr!Phe PheTyr! PheTyr!ArgGlu (SEQ ID NO:21) AspLysPheTyr!Val PheTyr! PheTyrLeu! PheTyrIleLeu! PheTyr! (SEQ ID NO:22)Asp LysPheTyr!Val PheTyr! PheTyrIleLeu! PheTyrIle! PheTyr! (SEQ IDNO:82) ValIle! PheTyr! PheTyrLeu! PheTyrIleLeu!Phe ArgThr!Xaa ThrAsn!(SEQ ID NO:83) ValIle! PheTyr! PheTyrIleLeu! PheTyrIle!Phe ArgThr!XaaThrAsn! (SEQ ID NO:84) ValIle! PheTyr! PheTyrIleLeu!PheTyrIleLeu!PheArgXaa ThrAsn! (SEQ ID NO:85) ValIle! PheTyr! PheTyrLeu!PheTyrIleLeu! PheTyr! ArgThr! GluAspVal! ThrAsn! (SEQ ID NO:86) (g) GluPheTyr!IleAsn CysSer!GlyLys (SEQ ID NO:25) PheTyr!IleAsnCysGlyLysAlaValIle! (SEQ ID NO:26) (h) Arg ValIle! AlaGly! ArgGln! ValIle!CysLys(SEQ ID NO:27)Arg ValIle!Xaa ArgGln! ValIle!CysXaaXaaAsp (SEQ ID NO:28)GlyLys ValAlaIle!XaaXaaXaaArg ValAlaIle!XaaXaaXaaCysLys (SEQ ID NO:29)(i) ArgLysAsn!Trp ThrAla! ThrAlaSer! PheTyrLeu!Leu LysArg! (SEQ IDNO:87) PheTyr!Leu LysArg! AlaSer!ArgLeu AsnIle!Cys (SEQ ID NO:31)AsnIle!CysSer IleVal! ProSer!Gly (SEQ ID NO:32) Trp ThrAla! ThrAlaSer!PheTyrLeu!LeuLys AlaSerValIleLeu!XaaLeu (SEQ ID NO:88) Trp ThrAlaSer!ThrAlaSer! PheTyrLeu!LeuLys AlaSerIleLeu!XaaLeu (SEQ ID NO:89) TrpThrAla! ThrAlaSer!XaaLeuLysXaaXaaLeuXaaCys (SEQ ID NO:90) (j) PheTyr!PheTyr! AsnAsp!GluIleGlnSer (SEQ ID NO:36) PheTyr!Pro PheTyr! PheTyr!PheTyr! AsnAsp!Glu (SEQ ID NO:37) (k) GlySerAla ValIleLeu!CysXaa PheTyr!(SEQ ID NO:38)SerAla ValIle!CysXaa PheTyr!XaaMet (SEQ ID NO:39) (l)AsnSer AsnAla!TrpLeu ProAla!Val (SEQ ID NO:40) (m) ValLeuIle!ProGluAspTyrSerPhe!ProArgProGly (SEQ ID NO:41)ValLeuIle!ProXaaProArgProGlyXaaCys (SEQ ID NO:91) ProGluAspTyrSerPhe!ProArgProGly ThrGlnSer!Cys (SEQ ID NO:43) (n) AspProHisPheTyr!Cys AlaGly!Trp (SEQ ID NO:44)Pro HisPheTyr!Cys AlaGly!TrpAsp(SEQ ID NO:45) AspProXaaCys AlaGly!TrpAsp (SEQ ID NO:46)CysXaaXaaXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:47)CysXaaXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:48)CysXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:49)CysXaaXaaCysXaaXaaXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:50)CysXaaXaaCysXaaXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:51), andCysXaaXaaCysXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:52).
 16. A methodaccording to claim 12, wherein said peptide sequence is selected fromthe group consisting of:(f) TyrPhePhe PheTyr!ArgGlu (SEQ ID NO:18)AspLysTyr!Val PheTyr! PheTyrLeu! PheTyrIleLeu! PheTyr! (SEQ ID NO:92) AspLysTyr!Val PheTyr! PheTyrIleLeu! PheTyrIle! PheTyr! (SEQ ID NO:93)ValIle!Tyr PheTyrLeu! PheTyrIleLeu!Phe ArgThr!Xaa ThrAsn! (SEQ ID NO:94)ValIle!Tyr PheTyrIleLeu! PheTyrIle!Phe ArgThr!Xaa ThrAsn! (SEQ ID NO:95)ValIle!Tyr PheTyrIleLeu! PheTyrIleLeu!PheArgXaa ThrAsn! (SEQ ID NO:96)Val PheTyr! PheTyrLeu! PheTyrIleLeu! PheTyr! ArgThr! GluAspVal! ThrAsn!(SEQ ID NO:97) Val PheTyr! PheTyrIleLeu! PheTyrIle! PheTyr! ArgThr!GluAspVal! ThrAsn! (SEQ ID NO:98) Val PheTyr! PheTyrIleLeu!PheTyrIleLeu! PheTyr!Arg GluAspVal! ThrAsn! (SEQ ID NO:99) (n)CysXaaXaaXaaAspProXaaCysXaaTrpAsp (SEQ IDNO:48)CysXaaXaaAspProXaaCysXaaTrpAsp (SEQ ID NO:49)CysXaaXaaCysXaaXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:51), andCysXaaXaaCysXaaXaaAspXaaXaaCysXaaTrpAsp (SEQ ID NO:52).
 17. A methodaccording to claim 1, wherein said polypeptide comprises an amino acidsequence selected from SEQ ID NO:54, 56, 58, 60, 62 and
 64. 18. A methodaccording to claim 12, wherein said polypeptide comprises SEQ ID NO:54.19. A method according to claim 1, wherein said polypeptide comprisesSEQ ID NO:56.
 20. A method according to claim 12, wherein saidpolypeptide comprises SEQ ID NO:58.
 21. A method according to claim 12,wherein said polypeptide comprises SEQ ID NO:60.
 22. A method accordingto claim 12, wherein said polypeptide comprises SEQ ID NO:62.
 23. Amethod according to claim 12, wherein said polypeptide comprises SEQ IDNO:64.